Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11][C:12]#[C:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[CH2:1]([O:8][CH2:9][C@H:10]([OH:27])[CH2:11]/[CH:12]=[CH:13]\[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CC[C@@H](O)COCc2ccccc2)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC(C)(C)OC(=O)N1CCC(/C=C\C[C@@H](O)COCc2ccccc2)CC1
Reaction time: 0.67 h

Procedure:
The alcohol from step 1 of this example (9.1 g, 24.4 mmol) was dissolved in EtOAc (100 ml) and quinoline (0.48 ml, 4.03 mmol) was added. Lindlar's catalyst (1.04 g) was added and the vessel evacuated and refilled three times with H2. The slurry was stirred under a H2 atmosphere for 40 min. The starting material was completely consumed. The mixture was filtered through CELITE and rinsed with EtOAc (4×50 ml). The volume of EtOAc was reduced ˜80% in vacuum. The remaining solution was diluted with ether (100 ml) and washed with 2N HCl (100 ml). The aqueous fraction was re-extracted with ether (2×50 ml), organics combined and washed with 15 ml 2 N HCl. The organic fraction was washed with saturated aqueous NaHCO3, brine, dried over MgSO4, filtered, and stripped. The resulting oil was purified by chromatography on SiO2 30% eluting with EtOAc:Hexanes to give the titled compound.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:21].C(=O)([O-])[O-].[Na+].[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>[CH:20]([C:22]1[O:26][CH:25]=[C:24]([C:2]2[C:12]3[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:23]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2coc(C=O)c2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2coc(C=O)c2)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.18 g, 3.60 mmol), 5-formylfuran-3-boronic acid pinacol ester (800 mg, 3.60 mmol), saturated aqueous sodium carbonate solution (15 ml), and tetrakis(triphenylphosphine)palladium(0) (118 mg, 0.102 mmol) in ethylene glycol dimethyl ether (20 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (900 mg, 72.6%) as an oil.
Reaction SMILES: O[C:2]1([C:28]([F:31])([F:30])[F:29])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)=[N:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][S:13]([C:10]1[CH:9]=[CH:8][C:7]([N:5]2[CH:6]=[C:2]([C:28]([F:30])([F:29])[F:31])[N:3]=[C:4]2[C:17]2[CH:22]=[CH:21][C:20]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)(=[O:14])=[O:15]
Reactant: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccc(-c3cccs3)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(-n2cc(C(F)(F)F)nc2-c2ccc(-c3cccs3)cc2)cc1
Yield: 63.9 %

Procedure:
A mixture of 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-[4-(2-thienyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole (0.345 g, 0.74 mmol) and p-toluenesulfonic acid monohydrate (0.035 g) in toluene (40 mL) was heated to reflux for 7 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in CH2Cl2 (50 mL) and the whole washed with water, aqueous NaHCO3 (30 mL), and brine. After dried over Na2SO4, and concentration in vacuo. The crude mixture was purified by flash chromatography eluting with hexane/ethyl acetate (2/1). The resulting solid was recrystallized from ethyl acetate-hexane to give the title compound (0.212 g, 63.9% yield).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([OH:18])=O)[C:3]1=[O:23].[F:24][C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.N1C=CC=CC=1>O=S(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:16]([NH:31][C:28]2[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=2)=[O:18])[C:3]1=[O:23]
Reactant: Nc1ccc(F)cn1
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)O)ccc1C)c(=O)n2C
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)Nc3ccc(F)cn3)ccc1C)c(=O)n2C
Reaction time: 0.5 h

Procedure:
A solution of 3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoic acid 29 (154 mg, 0.5 mmol) in SOCl2 (1 mL) is heated at reflux for 2 h. Excess SOCl2 is removed in vacuo and the resultant solid is added to a solution of 5-fluoropyridin-2-amine (112 mg, 1 mmol) and pyridine (0.4 mL, 5 mmol) at rt. The resulting mixture is stirred for 30 min and evaporated. The residue is purified by preparative LC/MS to give the desired product M32 as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.28 (m, 1H), 8.04 (s, 1H), 7.95 (dd, J=8, 2 Hz, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.65 (dt, J=9.1, 2.9 Hz, 1H), 7.57 (s, 1H), 7.48 (d, J=8 Hz, 1H), 3.8 (s, 3H), 2.73 (s, 3H), 2.32 (s, 3H); LC/MS (M+1, m/z): 403.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:12][C:13](=[O:15])[NH:14][C:7]=12.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:21]=1[N:30]=[C:31]=[O:32]>>[F:19][C:20]1[C:21]([NH:30][C:31]([NH:1][C:2]2[CH:18]=[CH:17][CH:16]=[C:4]([O:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]4[NH:12][C:13](=[O:15])[NH:14][C:7]=34)[CH:3]=2)=[O:32])=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1
Product: O=C(Nc1cccc(Oc2ccnc3[nH]c(=O)[nH]c23)c1)Nc1cc(C(F)(F)F)ccc1F
Yield: 20 %

Procedure:
Method G was used with 7-(3-aminophenoxy)-1H-imidazo[4,5-b]pyridin-2(3H)-one and 2-fluoro-5-trifluoromethyl-phenylisocyanate to afford the title compound (15 mg, 20%). 1H-NMR (DMSO), δ (ppm), J (Hz): 6.45 (d, 1H, HPyr, J=5.9), 6.79 (s, 1H, Harom5′, J=2.1, J=8.0), 7.20 (d, 1H, Harom 4 or 6, J=7.9), 7.21-7.41 (m, 3H, Harom 3′, Harom 2, Harom 6 or 4), 7.50 (t, 1H, Harom 5, J=10.7), 7.79 (d, 1H, HPyr), 8.55 (d, 1H, Harom 4′, J=7.2), 8.93 (s, 1H, NHurea), 9.38 (s, 1H, NHurea), 11.23 (s, 1H, NHim), 11.42 (s, 1H, NHim); MS-LC, Rf=7.64 min, (C20H13F4N5O3), m/z: 448.1 [M++1], 100.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH2:26])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:36]1C[O:39][CH2:38][CH2:37]1>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:24]=[CH:23][C:22]([CH2:25][NH:26][C:38](=[O:39])[CH:37]=[CH2:36])=[CH:21][CH:20]=2)=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)NCc1ccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)cc1
Yield: 23 %

Procedure:
N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide was prepared from (4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine, triethylamine instead of N,N-diethylethanamine, THF instead of methylpyrrolidin-2-one and dichloromethane using Method G (23% yield). HPLC: 93%, RT=4.014 min. MS: m/z=423 [M+H]+, RT=3.16 min. 1H-NMR (DMSO-d6) δ 8.99 (s, 1H), 8.36 (d, 1H), 8.18 (s, 1H), 8.08 (d, 2H), 7.89-7.83 (m, 4H), 7.65-7.48 (m, 7H), 7.25 (d, 1H), 6.80 (dd, 1H), 6.69 (d, 1H), 6.05 (d, 1H), 4.98 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][NH:21][CH:22]2[CH2:25][CH3:26])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:21]3[CH2:20][CH2:19][C:18]4[C:23](=[CH:24][C:15]([F:14])=[CH:16][CH:17]=4)[CH:22]3[CH2:25][CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CCC1NCCc2ccc(F)cc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CCC1c2cc(F)ccc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-fluoro-1-ethyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4]O.C(N(CC)CC)C.S([Cl:25])(C)(=O)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[C:3]=1[CH2:4][Cl:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)Nc1cccc(C)c1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(C)c1CCl
Reaction time: 0.5 h

Procedure:
To a suspension of 2-methyl-6-acetamidobenzyl alcohol (30 g) and triethylamine (46.54 ml) in methylene chloride (300 ml) was added dropwise mesyl chloride (14.25 ml) below 8° C. The mixture was stirred under ice cooling for 30 minutes and then at room temperature for 20 minutes. The reaction mixture was washed with 1N-hydrochloric acid solution, water and saturated sodium bicarbonate aqueous solution, dried over magnesium sulfate and evaporated in vacuo. The residue was suspended in n-hexane and the precipitates were collected by filtration and dried to give 2-methyl-6-acetamidobenzyl chloride (19.28 g).
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]3CCC[CH2:19][C:13]=3[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1SC([Br:37])=C(C)C=1C(OCC)=O.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([NH:10][C:11]2[S:15][C:14]([Br:37])=[C:13]([CH3:19])[C:12]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)c1c(N)sc(Br)c1C
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc(Br)c1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (Intermediate 35) and benzenesulphonyl chloride
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)([OH:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:18]N1C(=O)CCC1=O.O>CN(C=O)C>[Br:18][C:15]1[S:14][C:13]([C:10]([OH:12])([CH3:11])[CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])=[N:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(O)(CO[Si](C)(C)C(C)(C)C)c1nccs1
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)(CO[Si](C)(C)C(C)(C)C)c1ncc(Br)s1
Temperature: 25 °C
Yield: 22.2 %

Procedure:
The product of Step 1 (364 mg, 1.331 mmol) was dissolved in DMF (2 ml). N-bromosuccinimide (284 mg, 1.597 mmol) was added, and the solution was maintained 2 h at rt. Water was added and the mixture extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated in vacuo. Purification via silica gel column chromatography (0%-10% EtOAc:hexanes) afforded 2-(5-bromo-1,3-thiazol-2-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}propan-2-ol (104 mg, 22%) as a white solid. MS ESI: [M+H]+ m/z 352, 354.
Reaction SMILES: [CH:1]([NH:4][C:5]([NH:7][CH:8]([CH3:10])[CH3:9])=[Se:6])([CH3:3])[CH3:2].Cl[CH2:12][C:13](Cl)=[O:14].N1C=CC=CC=1>O1CCCC1>[CH:1]([N:4]1[C:13](=[O:14])[CH2:12][Se:6][C:5]1=[N:7][CH:8]([CH3:10])[CH3:9])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=[Se])NC(C)C
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)N=C1[Se]CC(=O)N1C(C)C
Yield: 101.1 %

Procedure:
0.42 g (2.0 mmol) of N,N′-diisopropyl selenourea were dissolved in 20 mL of tetrahydrofuran. 0.08 mL (1.0 mmol) of chloroacetyl chloride were added to the solution, and after stirring well, the mixture was allowed to react at 0 degrees Celsius for one hour. 0.09 mL (1.0 mmol) of pyridine was then added to the reaction mixture, followed by stirring at 0 degrees Celsius for additional 2 hours. The reaction mixture was extracted by an ordinary method, washed with water and dried, and the solvent was distilled off. As a result, 0.25 g of 3-isopropyl-2-isopropylimino-1,3-selenazolidin-4-one were obtained. The purity was 98.7%, and the yield was 100%.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[N:36]1[CH:41]=[CH:40][C:39]([CH:42]=[O:43])=[CH:38][CH:37]=1.[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([CH:42]([C:39]2[CH:40]=[CH:41][N:36]=[CH:37][CH:38]=2)[OH:43])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1ccncc1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(O)c3ccncc3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 4-pyridine carboaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])=[O:4].[CH2:18](OC1C=C(C=C(N)C=1)C(OCC=C)=O)[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH3:17])[C:3]([C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:20][CH:19]=[CH2:18])=[O:8])=[O:4]
Reactant: C=CCOC(=O)c1cc(N)cc(OCC=C)c1
Reactant: CN(C)C(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Product: C=CCOC(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C

Procedure:
2-Dimethylaminocarbonyl-3-nitrobenzoic acid (1 g) was to the allyl ester by a similar method to that described in example 1 for the formation of allyl 3-allyloxy-5-aminobenzoate giving allyl 2-dimethylaminocarbonyl-3-nitrobenzoate (0.88 g). Nmr (DMSO-d6): δ 2.45 (s, 3H); 2.97 (s, 3H); 4.79 (dd, 2H); 5.28-5.47 (m, 2H); 5.9-6.1 (m, 1H); 7.81 (t, 1H); 8.28-8.4 (dq, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][OH:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.Cl[C:18]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:22][CH:21]=[CH:20][N:19]=1>>[CH3:1][NH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([O:13][CH2:14][CH2:15][O:16][C:18]3[C:23]([N:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[N:22][CH:21]=[CH:20][N:19]=3)[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CNc1ccc2cccc(OCCO)c2n1
Reactant: Clc1nccnc1N1CCNCC1
Product: CNc1ccc2cccc(OCCOc3nccnc3N3CCNCC3)c2n1
Yield: 31 %

Procedure:
The title compound was prepared according to the procedure of Example 90, Step 2, starting from the product obtained in Step 2 above and 2-chloro-3-( (1-piperazinyl)piperazine (from Example 90, Step 1). The crude product was purified by column chromatography (gradient: 1% NH4OH in EtOAc/MeOH (90:10) to 1% NH4OH in EtOAc/MeOH (80:20) in first purification step and gradient 0.5% NH4OH in CHCl3/MeOH (95:5) to 1% NH4OH in CHCl3/MeOH (90:10) in second purification). Yield 31%; mp 54.0-56.5° C.; MS m/z 381 (M+H)+. Anal. (C20H24N6O20.5 H2O) C, H, N.
Reaction SMILES: [CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:23]=3)[C:8](=[O:20])[C:9]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:10]([OH:11])[C:5]=2[CH:4]=1)[CH3:2].IC.[H-].[Na+].O1CCC[CH2:42]1>C(OCC)(=O)C>[CH2:1]([C:3]1[S:36][C:6]2[N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[C:29]([C:34]#[N:35])=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[C:8](=[O:20])[C:9]([CH3:42])([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C1CCOC1
Reactant: CCc1cc2c(O)c(CCc3ccccc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)C(C)(CCc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 4′-{[2-ethyl-4-hydroxy-6-oxo-5-(2-phenylethyl)thieno[2,3-b]pyridin-7(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), iodomethane (0.076 mL), 60% sodium hydride (0.049 g) and tetrahydrofuran (15 mL) was stirred at room temperature for 20 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.32 g, 62%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@H:31]([C:34]([NH2:36])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@H:31]([C:34]([NH2:36])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: NC(=O)[C@H](CO)NC1=NC(=O)SC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: NC(=O)[C@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 15.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (893 mg) in 2-propanol (20 mL) were added N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-serinamide (1.07 g) and piperidinium acetate (195 mg). The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (217 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8](S)=[N:9][C:10](C)=[C:5]2[C:4]([C:13]2[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=2)=[N:3]1.[CH3:21][NH2:22]>C(O)C.C(OCC)(=O)C>[CH3:21][NH:22][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:13]3[O:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[C:5]=12
Reactant: Cc1nc(S)nc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNc1ncnc2c1c(-c1ccc([N+](=O)[O-])o1)nn2C

Procedure:
A mixture of 3.0 grams of 1-methyl-4-methyl-mercapto-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine, 50 milliliters of a 33 % solution of methylamine in ethanol and 20 milliliters of ethyl acetate was heated at reflux for 1 hour and cooled. The crystalline product formed was collected, washed with ethanol and dried. Recrystallisation from ethyl acetate gave 4-methylamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo[3,4-d]pyrimidine having melting point 280°C. identical to the product obtained in Example 13.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][CH2:14]OC)=[C:8]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)[C:7]([CH3:22])=[CH:6]2.Cl.O1CCOCC1.FC1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:8]1[C:7]([CH3:22])=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]=1[O:13][C:14]1[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][CH:32]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COCOc1c(-c2ccco2)c(C)cc2cc(OC)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccco3)c(C)cc2c1
Yield: 36.6 %

Procedure:
2-(6-Methoxy-1-methoxymethoxy-3-methyl-naphthalen-2-yl)-furan (213) (0.54, 1.8 mmol), 4 N HCl/Dioxane (6 mL), 4-fluorobenzaldehyde (0.23 mL, 2.17 mmol), Cs2CO3 (1.47 g, 4.53 mmol) and DMSO (8 mL) were reacted as described above to give 0.236 g (36%) of the title compound (214) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.48 (s, 3H), 3.93 (s, 3H), 6.34 (s, 2H), 6.84 (d, J=8.6 Hz, 2H), 7.04 (dd, J1=2.4 Hz, J2=9.2 Hz, 1H), 7.11-7.12 (m, 1H), 7.39 (s, 1H), 7.57 (s, 1H), 7.69-7.73 (m, 3H), 9.84 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([F:13])[C:3]=1[O:14]COCCOC.C([Li])CCC.[CH:26](N1CCCCC1)=[O:27]>C1COCC1.CCCCCC>[F:13][C:4]1[C:3]([OH:14])=[C:2]([CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:26]=[O:27]
Reactant: O=CN1CCCCC1
Reactant: CCCCOc1ccc(Br)c(OCOCCOC)c1F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(C=O)c(O)c1F
Reaction time: 1 h
Yield: 69.9 %

Procedure:
21.0 g (59.3 mmol) of 1-bromo-4-butoxy-3-fluoro-2-(2-methoxyethoxymethoxy)benzene (9) are dissolved in 200 ml of THF and treated at −78° C. with 37 ml (60 mmol) of a 15% strength solution of n-butyllithium in hexane. After 1 h, 6.8 ml (61 mmol) of N-formylpiperidine are added dropwise in 50 mmol of THF. The mixture is subsequently stirred for 1 h, and the mixture is allowed to thaw. After hydrolysis, the solution is acidified and extracted with MTBE. The combined organic phases are washed with water and dried over sodium sulfate. The solvent is removed in vacuo, the residue is taken up in 150 ml of THF, and after addition of 30 ml of conc. hydrochloric acid the mixture is stirred at room temperature overnight. The mixture is taken up in MTBE and washed with water (pH 5). The solvent is removed in vacuo and the crude product is filtered through silica gel using MTBE. 8.80 g (53%, 2 stages) of 3-fluoro-4-butoxy-2-hydroxybenzaldehyde (11) are obtained as a slightly violet solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:13]=NN(C)C=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(B2OC(C)(C)C(C)(C)O2)=C(C=1)C(OC)=O.[Cl:38][C:39]1[N:44]=C(Cl)C=[CH:41][N:40]=1>>[Cl:38][C:39]1[N:44]=[C:12]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:13]=[CH:41][N:40]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Agent: COC(=O)c1cc(C)ccc1B1OC(C)(C)C(C)(C)O1
Product: COC(=O)c1cc(C)ccc1-c1ccnc(Cl)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate and 2,4-dichloropyrimidine. ESI-MS (m/z): 263 [M+1]+.