Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH2:30])[CH:17]=2)=[CH:10][CH:9]=1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:38]1([CH2:51][O:52][C:53](Cl)=[O:54])[C:50]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]=2[CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([O:4][C:5](=[O:31])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:18]([NH:30][C:53]([O:52][CH2:51][C:38]3[C:50]4[CH2:49][C:48]5[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:42]=4[CH:41]=[CH:40][CH:39]=3)=[O:54])[CH:17]=2)=[CH:12][CH:13]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(N)c2)cc1
Reactant: O=C(Cl)OCc1cccc2c1Cc1ccccc1-2
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)COc1ccc(COc2ccc(C(=O)c3ccccc3)c(NC(=O)OCc3cccc4c3Cc3ccccc3-4)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
4-(3-Amino-4-benzoylphenoxymethyl)phenoxyacetic acid allyl ester (4.74 g, 11.4 mmol) and pyridine (1.09 g, 13.7 mmol, 1.2 equiv) were dissolved in 60 mL of CH2Cl2. The resulting yellow solution was cooled to 0° C., and fluorenylmethoxycarbonyl chloride (2.65 g, 1.14 mmol, 1.05 equiv) was added. The resulting solution was stirred at 0° C. for 15 min and then at ambient temperature for 1 h. The solution was diluted with CH2Cl2 (150 mL), extracted twice with 1N aqueous sodium bisulfate (100 mL), once with dilute aqueous sodium chloride (100 mL), and then concentrated to give a yellow foam. The unpurified product was crystallized from CH2Cl2 and hexanes to give 4.87 g (79% yield) purified material as a white solid: mp 96.5°-97.5° C. Rf 0.45 (CH2Cl2); IR (film from CH2Cl2, partial) 3230(b), 1740, 1610, 1575 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 4.32 (t, 1, J=7.4), 4.44 (s, 1, J=0.5), 4.71 (dd, 2, J=1.2, 5.9), 5.11 (s, 2), 5.26 (dd, 1, J=1.2, 10.4), 5.30 (dd, 1, J=1.4, 17.2), 5.85-598 (m, 2), 6.58 (dd, 2, J=2,5m 8.9) 6.92 (d, 2, J=8.8, 6.92 (q, 2, J=4.8, 9.6), 7.30-7.59 (m, 8), 7.63-7.70 (m,5), 7.76 (d, 2, J=8.9), 7.77 (d, 2, J=7.5), 8.29 (d, 1, J=2.3). 13C NMR (75.5 MHz, CDCl3) δ 47.3, 65.6, 66.2, 67.9, 70.0, 104.4, 109.6, 115.2, 115.8, 119.5, 120.4, 125.6, 127.5, 128.1, 128.8, 129.6, 129.8, 131.7, 131.9, 137.6, 140.0, 141.6, 144.1, 144.6, 154.1, 158.5, 164.1, 167.8, 199.1. Anal. Calcd for C40H33NO7 : C, 75.10; H, 5.20; N, 2.19. Found: C, 75.21; H, 5.33; N, 2.28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=3)[N:11]=2)[N:8]=1.[Cl:22]N1C(=O)CCC1=O>C(#N)C.O.C([O-])(O)=O.[Na+]>[Cl:22][C:9]1[N:7]2[N:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]2=[N:11][C:10]=1[C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)cn2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1ccc2nc(-c3ccc(C)c([N+](=O)[O-])c3)c(Cl)n2n1
Temperature: 60 °C
Yield: 98.9 %

Procedure:
To a stirred solution of 6-methoxy-2-(4-methyl-3-nitrophenyl)imidazo[1,2-b]pyridazine (0.250 g, 0.879 mmol) in acetonitrile (20 mL) is added N-chlorosuccinimide (0.879 mmol) and the mixture is heated at 60° C. for 8 hours. The reaction mixture is diluted with water (50 mL), and sat. aqueous NaHCO3 (50 mL). The precipitate that forms is collected by filtration, washed with water (3×25 mL) and dried under vacuum to give the title compound (0.277 g, 98% yield) as a yellow solid: Rf 0.60 (1:1 EtOAc:hexanes); LCMS (m/z)=319.3, 321.2 [M+H]+, tR=3.02 min.
Reaction SMILES: NC1CCC2C(=CC(OC)=C([O:12]C)C=2)C1.[CH:16]1([N:22]=[C:23]=[N:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C(NCC(O)=O)(OC(C)(C)C)=O>C(Cl)Cl>[C:23]([NH:22][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)([NH:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:12]
Reactant: COc1cc2c(cc1OC)CC(N)CC2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 2 h

Procedure:
2-amino-6,7-dimethoxy tetraline (0.4 g; 2.07 mmoles) was dissolved in 20 ml CH2Cl2. Dicyclohexylcarbodiimide (0.4 g; 2.07 mmoles) and carbotertbutoxyglycine (0.36 g; 2.07 mmoles) were added to the solution. The solution was kept under stirring for 2 hours. Dicyclohexylurea that formed was then filtered off. The filtrate was extracted with a saturated solution of NaHCO3, diluted HCl and H2O till neutrality was reached. The organic phase separated and dried was concentrated under vacuum. The residue thus obtained was chromatographed on a silica gel column, eluting with CHCl3 --AcOEt, 1:1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[Cl-].[O:18]([C:25]1[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=1)[CH:28]=[N+:29]([CH3:31])[CH3:30])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O(C1C=C(C=CC=1)C=O)C1C=CC=CC=1.CNC>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:28]([N:29]([CH3:31])[CH3:30])[C:27]2[CH:32]=[CH:33][CH:34]=[C:25]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:26]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:6][CH:7]=1
Reactant: C[N+](C)=Cc1cccc(Oc2ccccc2)c1
Reactant: Fc1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: CNC
Agent: O=Cc1cccc(Oc2ccccc2)c1
Agent: [Cl-]
Product: CN(C)C(c1cccc(Oc2ccccc2)c1)c1c(-c2ccc(F)cc2)[nH]c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 2-(4-fluoro-phenyl)-1H-indole and (3-phenoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3-phenoxy-benzaldehyde and dimethylamine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10]([NH2:13])[CH2:11][CH3:12]>O>[CH3:9][O:8][C:4]1[C:5]([NH:13][CH2:10][CH2:11][CH3:12])=[CH:6][CH:7]=[CH:2][N:3]=1
Reactant: CCCN
Reactant: COc1cccc(Cl)n1
Solvent: O
Product: CCCNc1cccnc1OC
Yield: 40.2 %

Procedure:
In the same reacting apparatus as in Example 1, 20 g of 2-chloro-6-methoxypyridine, 25 g of n-propylamine and 80 ml of water were charged and they were subjected to reacting each other at 180° C. for 5 hours. After completion of the reaction, the similar experimental procedure was carried out to give 9.3 g of 2-methoxy-n-propylaminopyridine of b.p. 90°-91° C./4 mmHg.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][CH:9]([CH2:10][CH:11]2[O:16][CH2:15][CH2:14][O:13][CH2:12]2)[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][I:8])[O:2]1.[C:19]1([P:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(#N)C.CCN(C(C)C)C(C)C>[I-:8].[CH2:1]1[CH2:18][O:17][CH:9]([CH2:10][CH:11]2[O:16][CH2:15][CH2:14][O:13][CH2:12]2)[CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][P+:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:2]1
Reactant: ICCCCC1OCCOC1CC1COCCO1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: [I-]
Product: c1ccc([P+](CCCCC2OCCOC2CC2COCCO2)(c2ccccc2)c2ccccc2)cc1
Yield: 70.3 %

Procedure:
A solution of 4.13 g (11.2 mmol) of 5,8-bis(ethylenedioxy)nonyl iodide and 2.93 g (11.2 mmol) of triphenyl phosphine in 25 ml of acetonitrile was buffered with a few drops of Hunig's Base and heated under nitrogen at 65° for 24 hours. The solvent was removed in vacuo until the resulting gum began to foam. This viscous gum was taken up in 25 ml of 3-pentanone and the resulting solution was seeded with a crystal of the salt and allowed to stand until crystallization was complete. Filtration afforded 4.98 g of salt. The mother liquors were placed in the freezer overnight and another 0.64 g of salt crystallized. Yield (5.62 g, 80%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.N1C=CN=C1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[O:9][CH2:10][CH2:11][O:12]2)=[CH:6][CH:7]=1
Reactant: OCC1(c2ccc(Br)cc2)OCCO1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC1(c2ccc(Br)cc2)OCCO1
Temperature: 23 °C
Reaction time: 12 h
Yield: 97.4 %

Procedure:
73.5 g 2-(4-Bromophenyl)-1,3-dioxolane-2-methanol are dissolved in 800 ml N,N-dimethylformamide. 38.6 g imidazole and 51.3 g tert-butyldimethylchlorosilane were added. It was stirred for 12 hours at 23° C. Afterwards, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. It was stirred for another 30 min. Then it was extracted with ethyl acetate twice. The combined organic layers were washed with brine and dried over sodium sulphate. The crude product was purified by column chromatography. 103.21 g product was obtained (97.5% of theory).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][CH:7]([C:9]([O:11][CH3:12])=[O:10])C)[C:3](O)=[O:4].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][CH:2]([CH2:6][CH2:7][C:9]([O:11][CH3:12])=[O:10])[C:3]([Cl:15])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)CC(Cl)C(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCC(Cl)C(=O)Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 7.6 g of 2-chloro-4-methoxycarbonyl valeric acid, 9.2 ml of thionyl chloride and 30 ml of toluene was stirred for 30 minutes at 80° C., followed by distilling off the solvent under reduced pressure to leave 2-chloro-4-methoxycarbonyl butyryl chloride. A mixture of this compound, 5.0 g of 2-benzylaminobenzophenone, 100 ml of ethyl acetate and 100 ml of a saturated aqueous solution of sodium hydrogencarbonate was stirred for 30 minutes at room temperature. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent, hexane:ethyl acetate=5:1) to give 1.2 g of 2-[N-benzyl-N-(2-chloro-4-methoxy carbonyl)butyryl]aminobenzophenone as an oily product.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12]OS(C2C=CC(C)=CC=2)(=O)=O)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@H:11]([OH:24])[CH2:12][N:28]2[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C[C@H](O)Cn2cc([N+](=O)[O-])nc2Cl)CC1
Yield: 66.4 %

Procedure:
(R)-2-Chloro-1-[2-hydroxy-3-(4-methylbenzene-sulfonyloxy)propyl]-4-nitroimidazole prepared in Example 8 (16.86 g, 44.86 mmol) and tert-butyl piperazine-1-carboxylate (8.36 g, 44.89 mmol) were dissolved in acetonitrile (100 ml). To the solution, triethylamine (6.3 ml, 45.2 mmol) was added followed by stirring under reflux for 6 hours. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. To the residue, water (100 ml) was added and extracted with ethyl acetate (100 ml) twice. The organic phases were combined, washed with water (100 ml) and a saturated saline solution (100 ml) in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/methanol=40/1) and then recrystallized from ethyl acetate/n-hexane to afford tert-butyl (S)-4-[3-(2-chloro-4-nitroimidazol-1-yl)-2-hydroxypropyl]piperazine-1-carboxylate (11.61 g, yield 66%) as a light yellow powder.
Reaction SMILES: IC1C=[CH:10][C:9]2[C:4](=CC=C[CH:8]=2)N=1.C([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)C>C(Cl)Cl.CCOC(C)=O>[C:16]([O:15][C:9]([CH3:8])([CH3:4])[CH3:10])([CH3:19])([CH3:18])[CH3:17]
Reactant: Ic1ccc2ccccc2n1
Reactant: CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
HClO4 (1.17 mL, 13.6 mmol) is added to a suspension of 48k (3.40 g, 9.06 mmol) in t-butyl acetate (100 mL) and DCM (150 mL). The reaction mixture is stirred at RT overnight then is diluted with EtOAc (150 mL). The solution is washed twice with aqueous 5% NaHCO3 solution, dried (MgSO4), filtered and concentrated under reduced pressure. The residue is purified by flash chromatography (Combi-Flash; EtOAc/hexane) to give t-butylether 481 (2.76 g, 71% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12]1([NH2:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:22][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: Nc1cccc2ccccc12
Reactant: O=C(O)c1cc(Cl)ccc1O
Product: O=C(Nc1cccc2ccccc12)c1cc(Cl)ccc1O
Yield: 65 %

Procedure:
Using 5-chlorosalicylic acid and 1-naphthylamine as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([O:5][C:6](=[O:49])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:48])[CH:16]([C:40]2[CH:45]=[CH:44][C:43]([C:46]#[N:47])=[CH:42][CH:41]=2)[N:17]2[CH:30]([CH2:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)[C:29](=[O:38])[N:20]3[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:19]3[C:18]2=[O:39])=[CH:9][CH:8]=1)(C)(C)C.C(Cl)Cl.C(C(O)=O)(F)(F)F>>[C:46]([C:43]1[CH:44]=[CH:45][C:40]([CH:16]([N:17]2[CH:30]([CH2:31][CH:32]3[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[C:29](=[O:38])[N:20]3[CH2:21][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[CH2:28][CH:19]3[C:18]2=[O:39])[C:15]([NH:14][CH2:13][C:10]2[CH:9]=[CH:8][C:7]([C:6]([OH:49])=[O:5])=[CH:12][CH:11]=2)=[O:48])=[CH:41][CH:42]=1)#[N:47]
Reactant: CC(C)(C)OC(=O)c1ccc(CNC(=O)C(c2ccc(C#N)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1ccc(C(C(=O)NCc2ccc(C(=O)O)cc2)N2C(=O)C3Cc4ccccc4CN3C(=O)C2CC2CCCCC2)cc1
Yield: 100 %

Procedure:
The above-described cyclized products 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid tert-butyl ester (diastereomers A and B) were treated with a 1:1 CH2Cl2 /CF3CO2H solution according to General Method 3 to afford 27 mg (100%) of 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid (diastereomer A) and 35 mg (100%) of 4-{[2-(4-cyano-phenyl)-2-(3-cyclohexylmethyl-1,4-dioxo-1,3,4,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-2-yl)-acetylamino]-methyl}-benzoic acid (diastereomer B).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([NH2:19])[C:15]([NH2:18])=[CH:16][CH:17]=2)[CH2:4][CH2:3]1.[OH2:20].[N:21]#[C:22]Br>C(O)(=O)C>[C:12]([OH:20])(=[O:11])[CH3:13].[C:10]([OH:11])(=[O:20])[CH3:9].[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[NH:18][C:22]([NH2:21])=[N:19][C:14]=3[CH:13]=2)[CH2:4][CH2:3]1
Reactant: N#CBr
Reactant: O
Reactant: CN1CCN(CCCOc2ccc(N)c(N)c2)CC1
Solvent: CC(=O)O
Product: CN1CCN(CCCOc2ccc3[nH]c(N)nc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 100 mL flasked was charged with 4-(3-(4-methylpiperazin-1-yl)propoxy)benzene-1,2-diamine (1.15 g, 4.35 mmol), water (50 mL) and acetic acid (2 mL) and stirred at room temperature for 15 minutes. The reaction mixture was placed in an ice bath and then charged with cyanogen bromide (0.526 g, 5 mmol). The reaction mixture was allowed to warm to room temperature and stirred over night. The reaction mixture was concentrated under reduced pressure and redissolved in acetone, dried over anhydrous sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to give 1.7 g of 5-(3-(4-methylpiperazin-1-yl)propoxy)-1H-benzo[d]imidazol-2-amine diacetate. This material was used without any further purification. MS (EI): 290 (MH+).
Reaction SMILES: C(OC([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)=O)C.C[Mg+].[Br-]>C1COCC1>[OH:35][C:32]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C:22]4=[O:27])=[CH:17][CH:16]=3)[C:10](=[O:28])[C:9]=2[N:8]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[N:7]=1)([CH3:33])[CH3:31]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(N3CCCCC3=O)cc1)C2=O
Agent: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)(C)O)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To 1-(4-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidin-1-yl)-phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.1, 0.2 mmol) in THF (15 mL) at 0° C. was added MeMgBr (0.21 mL, 0.6 mmol) and the reaction was stirred at rt for 24 h. The reaction was quenched with water and purified by HPLC to afford 47 mg (48%) of a white solid; Mass Spec (M+H)+ 475.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH:15]([CH2:17][O:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)[CH2:14][C:13]2=[O:29])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>O1CCOCC1.O>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH:15]([CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)[CH2:14][C:13]2=[O:29])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: COC(=O)c1ccc(OCC2CC(=O)N(c3ccc(OS(C)(=O)=O)cc3)C2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Oc1ccc(N2CC(COc3ccc(C(=O)O)cc3)CC2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.1 %

Procedure:
Methyl 4-[1-(4-methanesulfonyloxyphenyl)-2-pyrrolidon-4-yl]methoxybenzoate (1.78 g) is dissolved in dioxane (20 ml) and thereto is added a solution of sodium hydroxide (0.34 g) in water (5 ml). The mixture is stirred at room temperature for 16 hours. After adding conc. hydrochloric acid (about 0.7 ml), the reaction mixture is concentrated under reduced pressure. Water is added to the resulting residue and the precipitate is collected by filtration, washed with water and recrystallized from about 15% aqueous methanol to give the desired product (1.43 g), m.p. 199°-201° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Cl[C:14]1[CH:19]=[C:18]([S:20][CH3:21])[N:17]=[CH:16][N:15]=1>CN(C=O)C.C(OCC)(=O)C.O>[CH3:21][S:20][C:18]1[CH:19]=[C:14]([O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[N:15]=[CH:16][N:17]=1
Reactant: CSc1cc(Cl)ncn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CSc1cc(Oc2ccc([N+](=O)[O-])cc2)ncn1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 44 %

Procedure:
To a solution of 4-nitrophenol (8.04 g, 58 mmol) in DMF (36 ml) is added at 0° C. sodium hydride (2.5 g, 63 mmol, 60% in mineral oil) and stirring is continued for 30 minutes at r.t. A solution of 4-chloro-6-methylsulfanyl-pyrimidine (8.44 g, 52.5 mmol) in DMF (12 ml) is added and the reaction mixture is sealed in a reaction tube and heated in the microwave to 130° C. for 20 minutes. The reaction mixture is taken up in ethyl acetate and water. The organic phase is washed dried and evaporated. Recrystallization from ethyl acetate results in 6.08 g (44%) of an off-white powder of sufficient purity.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15](=[O:17])[NH:14][C:13]=3[CH:18]=2)[C:5]([CH3:19])=[CH:4][N:3]=1.Cl.[F:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH2:29])=[CH:24][C:23]=1[O:30][CH3:31].[C:32]([OH:38])([C:34]([F:37])([F:36])[F:35])=[O:33].ClC1N=CC=CN=1>CC(O)C>[F:35][C:34]([F:37])([F:36])[C:32]([OH:38])=[O:33].[F:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([NH:29][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:10]=[CH:11][C:12]4[O:16][C:15](=[O:17])[NH:14][C:13]=4[CH:18]=3)[C:5]([CH3:19])=[CH:4][N:3]=2)=[CH:24][C:23]=1[O:30][CH3:31]
Reactant: COc1cc(N)cc(C)c1F
Reactant: Cc1cnc(Cl)nc1Nc1ccc2oc(=O)[nH]c2c1
Agent: Cl
Agent: Clc1ncccn1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: COc1cc(Nc2ncc(C)c(Nc3ccc4oc(=O)[nH]c4c3)n2)cc(C)c1F
Temperature: 77.5 °C
Reaction time: 22 h

Procedure:
Into a three-neck round-bottom flask, 5-(2-chloro-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one (33.2 g, 120 mmol) and 4-fluoro-3-methoxy-5-methylbenzenamine hydrochloride (32.19 g, 168 mmol) were added, followed by i-PrOH (750 mL) and TFA (23.1 mL, 300 mmol). The reaction mixture was stirred under nitrogen atmosphere with gentle refluxing (note: with overhead stirrer at internal temperature of 75-80° C.). After 22 h, by LC-MS, the reaction was >95% complete (note: when ≦3% of the 2-chloropyrimidine starting material remained, the reaction did not progress much further even after another day or two). The reaction mixture was cooled to room temperature, precipitate was collected by filtration, washing with i-PrOH (˜50 mL×2). Compound 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one trifluoroacetate was obtained as a light tan color solid (still a little bit damp) and was added to a NaHCO3 aqueous solution (15.12 g (180 mmol) of NaHCO3 dissolved in 1 L of H2O). The aqueous suspension was stirred at rt overnight. Solid was collected by filtration, washing with H2O (˜150 mL×3), and was further dried under high vacuum. Free base compound 5-(2-(4-fluoro-3-methoxy-5-methylphenylamino)-5-methylpyrimidin-4-ylamino)benzo[d]oxazol-2(3H)-one was obtained as an off-white solid: 44.51 g (93.8% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])([O-:3])=[O:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:14]([O:13][C:6]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirred solution of 3,4-dinitrophenol (1 g) in dimethylformamide (30 mL) was treated with benzyl bromide (723 μL) and potassium carbonate (1.13 g). The reaction mixture was stirred at ambient temperature for 24 hours and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:4, v/v) to give 4-benzyloxy-1,2-dinitrobenzene (1.30 g) as a yellow solid. LC-MS (METHOD B): RT=3.31 minutes. 1HNMR [(CD3)2CO, ppm): δ 5.28 (s, 2H), 7.26-7.42 (m, 61), 7.57 (d, 1H), 8.12 (d, 1H).