Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.[NH2:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=1[O:33][CH3:34]>C(O)C.O.Cl>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 30.3 %

Procedure:
A mixture of 3.30 g (0.010 mole) of 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 2.006 g (0.012 mole) of 4-amino-3-methoxybenzoic acid and 200 mL of ethanol-water-hydrochloric acid (20:80:1) was refluxed for 18 hours, then concentrated under reduced pressure. The solid was washed with water and then purified by silica gel chromatography, eluting with dichloromethane-methanol-ammonium hydroxide (92:8:0.3) to give 1.400 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29](O)=[O:30])=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:29]([C:27]1[CH:26]=[CH:25][C:24]2[O:20][CH2:21][CH2:22][C:23]=2[CH:28]=1)=[O:30]
Reactant: O=C(O)c1ccc2c(c1)CCO2
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)CCO2

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 2,3-dihydro-benzofuran-5-carboxylic acid. MS: 406.4 (M+H).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:15]2[CH:14]=[N:13][C:12]([C:16](=O)[CH3:17])=[N:11][C:10]=2[CH:9]=[CH:8]1.Cl.[CH2:22]([NH2:24])[CH3:23].C([BH3-])#N.[Na+]>CCO>[CH2:22]([NH:24][CH:16]([C:12]1[N:13]=[CH:14][C:15]2[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:20])([CH3:19])[CH3:1])[CH:8]=[CH:9][C:10]=2[N:11]=1)[CH3:17])[CH3:23]
Reactant: CC(=O)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CCNC(C)c1ncc2c(ccn2COCC[Si](C)(C)C)n1
Temperature: 130 °C
Reaction time: 0.03 h

Procedure:
A microwave vial charged with 1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanone (1.50 g, 5.15 mmol), ethylamine hydrochloride (3.36 g, 41.2 mol), sodium cyanoborohydride (420.5 mg, 6.69 mmol), and anhydrous EtOH (40 mL) was stirred under microwave irradiation (300 Watts) at 130° C. for 2 min. The solid was filtered and rinsed well with EtOH. Volatile solvent from the filtrate was removed under reduced pressure. The resultant crude was redissolved in EtOAc and washed with 10% aqueous NaOH solution (2×), water, and brine. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude was triturated in DCM, and the insoluble solid was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and dried on high-vac to afford N-ethyl-1-(5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-d]pyrimidin-2-yl)ethanamine as an oil. 1H NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 7.50 (d, J=3.2 Hz, 1H), 6.65 (d, J=3.2 Hz, 1H), 5.50 (s, 2H), 4.09 (q, J=6.7 Hz, 1H), 3.46 (t, J=8.1 Hz, 2H), 2.57 (dd, J=11.2, 7.2 Hz, 1H), 2.46 (dd, J=11.2, 7.0 Hz, 1H), 2.08 (br s, 1H), 1.46 (d, J=6.7 Hz, 3H), 1.08 (t, J=7.1 Hz, 3H), 0.88 (t, J=8.1 Hz, 2H), −0.07 (d, J=0.9 Hz, 9H)); MS (ESI) m/z: 321.4 [M+1]+.
Reaction SMILES: C(O[C:5](=[O:14])[CH:6]=[C:7]([NH:12][CH3:13])[C:8]([F:11])([F:10])[F:9])(C)C.[CH2:15]([O:18][C:19]([C:21]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[Cl:35])([CH3:23])[CH3:22])=[O:20])[CH:16]=[CH2:17].Cl>C(#N)C>[CH2:15]([O:18][C:19]([C:21]([O:24][C:25](=[O:36])[C:26]1[CH:31]=[C:30]([N:32]2[C:5](=[O:14])[CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[N:12]([CH3:13])[C:33]2=[O:34])[CH:29]=[CH:28][C:27]=1[Cl:35])([CH3:23])[CH3:22])=[O:20])[CH:16]=[CH2:17]
Reactant: C=CCOC(=O)C(C)(C)OC(=O)c1cc(N=C=O)ccc1Cl
Reactant: CNC(=CC(=O)OC(C)C)C(F)(F)F
Agent: Cl
Solvent: CC#N
Product: C=CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 2.5 °C
Yield: 91.2 %

Procedure:
2.9 g of potassium tert.butylate (content 97%, 0.025 mols) are suspended in 169 g of dry acetonitrile (water content <0.01%) and cooled to 0-5° C. Subsequently, at 0-5° C., 36.2 g of 3-methylamino-4,4,4-trifluorobut-2-enoic acid isopropylester (content 98.3%, 0.17 mols) are added and maintained at this temperature for 30 minutes, whereby a red-brown solution is produced. Then, over the course of 15 minutes, at 0-5° C., 27.3 g of 5-isocyanato-2-chloro-benzoic acid 1-allyloxycarbonyl-1-methyl-ethyl-ester (content 99%, 0.084 mols) are dispensed in, whereby a dark brown solution is obtained. The latter is adjusted to pH 7 with 3.0 g of 1 N hydrochloric acid [content of desired product in the solution is 15.5%, which corresponds to a yield of 91.2%]. The solvent is subsequently distilled off in a vacuum, and the residue (68 g) is recrystallised in 200 g of isopropyl alcohol, whereby the inorganic salts are removed by hot filtration. After drying in a vacuum drying chamber at 60° C. for 12 hours, 32.8 g (82% of theory) of the desired product are isolated in a content of 98.7%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=C[C:20]2N(O)N=[N:23][C:21]=2[CH:22]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1(N)CC1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH:23][CH:21]1[CH2:22][CH2:20]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)NC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 369.9 %

Procedure:
To a mixture of (2S,4R)-4-Hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (6 g, 26 mmol), HOBt (0.8 g, 6 mmol) and DCC (5.97 g, 29 mmol) in DCM (260 mL) was added cyclopropylamine (2.1 mL, 31 mmol) and DIPEA (6.8 mL, 39 mmol). The mixture was stirred at rt for overnight. The insolubles were filtered off, the filtrate was concentrated and extracted into ethyl acetate. The organic layer was concentrated and dried to give 6 g of (2S,4R)-2-cyclopropylcarbamoyl-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:22]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:21]([CH2:31][O:32][CH2:33][CH3:34])=[N:20][C:14]=3[CH:15]=[N+:16]([O-])[C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[NH4+:36].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCl>[NH2:36][C:15]1[C:14]2[N:20]=[C:21]([CH2:31][O:32][CH2:33][CH3:34])[N:22]([CH2:23][C:24]([NH:27][C:28](=[O:30])[CH3:29])([CH3:26])[CH3:25])[C:13]=2[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:18][C:17]=2[N:16]=1
Reactant: [NH4+]
Reactant: CCOCc1nc2c[n+]([O-])c3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(C)=O
Reaction time: 5 h

Procedure:
N-[2-(7-Benzyloxy-2-ethoxymethyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide (1.77 g, 3.83 mmol) was dissolved in dichloromethane (100 mL) and aqueous ammonium hydroxide (10 mL) was added, followed by para-toluenesulfonyl chloride (0.73 g, 3.83 mmol). After stirring for 5 hours, the organic and aqueous phases were separated and the organic fraction was washed twice with saturated sodium bicarbonate and then once with brine. The organic fraction was then dried over sodium sulfate, filtered, and concentrated to give a dark orange solid. The solid was purified by flash column chromatography on silica gel (eluting with a gradient of 6-7.5% methanol in dichloromethane) followed by recrystallization from acetonitrile to provide 1.27 g of N-[2-(4-amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]acetamide as a white powder, mp 202.0-205.0° C.
Reaction SMILES: [CH2:1]([NH2:5])[C@@H:2]([NH2:4])[CH3:3].[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1.ClCCl>CC(C)CC(O)C>[NH2:4][C@@H:2]([CH3:3])[CH2:1][NH:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](N)CN
Solvent: ClCCl
Solvent: CC(C)CC(C)O
Product: Cc1ccc(S(=O)(=O)NC[C@H](C)N)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To 62.9 parts of (S)-1,2-propanediamine under a nitrogen atmosphere (temp. 0°-5° C.) was added dropwise over 7 hours a solution of 80.84 parts of 4-methylbenzenesulfonyl chloride in 1689 parts of dichloromethane. After stirring overnight at 20° C., the reaction mixture was washed with 250 parts of water (3×). The organic layer was separated, dried, filtered and evaporated. About 1 gram of the thus obtained product was recrystallized from 2-propanol. After cooling to 0° C,, filtering and drying, about 0.30 parts of crystals suitable for seeding were obtained. The remainder of the product was dissolved in 4-methyl-2-pentanol by heating just below the reflux temperature. The mixture was allowed to cool slowly and at about 30° C. was seeded with the previously obtained crystals. After further cooling to 0° C., the precipitate was filtered off and triturated with 2,2'-oxybispropane. The crystals were filtered off, dried in vacuo, yielding 50.75 parts (52.4%) of (S)-N-2-aminopropyl-4-methylbenzenesulfonamide; mp. 82°-86° C.; [α]20D =-1.10° (c =1% in methanol) (interm. 1).
Reaction SMILES: C(OC([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:14]1[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH:34]C(OCC)=O)=[C:23]([C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)[CH:24]=3)[CH:16]=[N:15]1)[CH2:10]2)=O)C.[OH-].[K+].O.NN.O>C(O)CO>[CH:11]12[NH:6][CH:7]([CH2:13][CH2:12]1)[CH2:8][CH:9]([N:14]1[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([C:25]4[S:26][C:27]5[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=5[N:29]=4)[C:22]([NH2:34])=[N:21][CH:20]=3)[CH:16]=[N:15]1)[CH2:10]2
Reactant: CCOC(=O)Nc1ncc(-c2cnn(C3CC4CCC(C3)N4C(=O)OCC)c2)cc1-c1nc2ccccc2s1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1ncc(-c2cnn(C3CC4CCC(C3)N4)c2)cc1-c1nc2ccccc2s1
Temperature: 200 °C

Procedure:
To a stirring solution of 3-[4-(5-benzothiazol-2-yl-6-ethoxycarbonylaminopyridin-3-yl)-pyrazol-1-yl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (7.1 mg, 0.013 mmol, 1 eq) and potassium hydroxide (22.2 mg, 0.396 mmol, 30 eq) in 1,2-ethanediol (3 mL), hydrazine hydrate (7 μL, 0.1 mmol, 10 eq) was added and the solution was stirred at reflux (T=200° C.) for 9 h. The reaction mixture was poured into water and extracted with ether. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep. TLC [Silicycle, 1000 μm, 20×20 cm plate, developed twice in a 8% 7N NH3(MeOH):CH2Cl2 solvent system.] The desired band was scraped from the plate, the silica gel was completely rinsed of all product, and the filtrate was concentrated in vacuo, giving the title compound as a yellow solid. MS (ES+): m/z=403.17 (40) [MH+]. HPLC: tR=2.37 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][CH:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[CH3:18])[N:12]3[N:25]=[CH:26][CH:27]=[C:11]3[N:10]=2)[CH:7]=1.P(Cl)(Cl)(Cl)=O.CN([CH:37]=[O:38])C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:28])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH2:16][CH:17]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[CH3:18])[N:12]3[N:25]=[CH:26][C:27]([CH:37]=[O:38])=[C:11]3[N:10]=2)[CH:7]=1
Reactant: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2ccnn12)N1CCOCC1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(CNc1cc(Nc2cc(Cl)ccc2F)nc2c(C=O)cnn12)N1CCOCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41 %

Procedure:
In a reaction flask, N5-(5-chloro-2-fluorophenyl)-N7-(2-morpholinopropyl)pyrazolo[1,5-a]pyrimidine-5,7-diamine (84 mg, 0.21 mmol) was dissolved in DMF (0.9 mL) then phosphorous oxychloride (58 uL, 0.62 mmol) was added slowly at room temperature. The reaction mixture was allowed to stir at room temperature for 2 days then quenched by addition to 6N NaOH solution. The pH of the mixture was adjusted with 6N HCl to pH=7-9. The solid was recovered by filtration and washed with water. The product, 5-(5-chloro-2-fluorophenylamino)-7-(2-morpholinopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde, was purified by preparative TLC (5% acetone/dichloromethane) to yield 37 mg of the desired product (41% yield). LCMS (M+1=433)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]=[C:14]([OH:19])[CH:13]=[C:12]3Br)=[CH:4][CH:3]=1.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH2:36][NH2:37])[CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2].O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[NH:37][CH2:36][C:32]2[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=2)=[CH:4][CH:3]=1
Reactant: Oc1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2n1
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: O=c1cc(NCc2cccc(C(F)(F)F)c2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 6-[bis(4-chlorophenyl)methyl]-4-bromoquinolin-2-ol (150 mg, 0.33 mmol, 1.00 equip), [3-(trifluoromethyl)phenyl]methanamine (85.78 mg, 0.49 mmol, 1.50 equip), Pd2(dba)3 (30 mg, 0.03 mmol, 0.10 equip), dppf (63.4 mg, 0.11 mmol, 0.35 equip), Cs2CO3 (266 mg, 0.82 mmol, 2.50 equip), and 1,4-dioxane (3 mL). The resulting solution was stirred overnight at 100° C. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). The resulting residue was recrystallized from ethyl acetate:petroleum ether in the ratio of 1:10 to yield 6-(bis(4-chlorophenyl)methyl)-4-((3-(trifluoromethyl)benzyl)amino)quinolin-2(1H)-one as an off-white solid.
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]=2)[NH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>CN(C=O)C>[F:26][C:27]([F:37])([F:36])[C:28]1[CH:35]=[CH:34][C:31]([CH2:32][N:6]2[C:7]3[C:12](=[CH:11][C:10]([O:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=3)[C:4]([CH:3]=[N:2][O:1][CH2:32][C:31]3[CH:30]=[CH:29][C:28]([C:27]([F:26])([F:36])[F:37])=[CH:35][CH:34]=3)=[CH:5]2)=[CH:30][CH:29]=1
Reactant: CCOC(=O)COc1ccc2[nH]cc(C=NO)c2c1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of the product of step 3 (280 mg, 1.068 mmoles) in DMF (2 ml), cesium carbonate (1.0 gm, 3.2 mmoles), 4-trifluoromethyl benzylbromide (510 mg, 2.13 mmoles were added and the reaction mixture was stirred at 25° C. for 2 hours. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure, The crude product was purified by column chromatography using 15% EtOAC in hexane as eluent to yield 350 mg (56%) of product as solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]1[CH2:37][CH2:36][C:13]2([O:17][N:16]=[C:15]([C:18]3[CH:23]=[N:22][C:21]4[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:20]=4[C:19]=3[NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:14]2)[CH2:12][CH2:11]1)=[N+]=[N-]>O1CCCC1>[CH:30]1([NH:29][C:19]2[C:18]([C:15]3[CH2:14][C:13]4([CH2:36][CH2:37][CH:10]([NH2:7])[CH2:11][CH2:12]4)[O:17][N:16]=3)=[CH:23][N:22]=[C:21]3[N:24]([CH2:27][CH3:28])[N:25]=[CH:26][C:20]=23)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(N=[N+]=[N-])CC4)C3)cnc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(N)CC4)C3)cnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium aluminium hydride (0.0018 mole) is taken in tetrahydrofuran. 5-(8-Azido-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-N-cyclohexyl-1-ethyl-1H-pyrazolo[3,4-b]pyridin-4-amine (0.00047 mole) (example 46) is added. The reaction mixture is stirred at room temperature overnight. It is quenched with aqueous sodium sulphate solution followed by ethyl acetate. The filtration is done through celite pad and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:16][OH:17])([O-:12])=[O:11].C(N(CC)CC)C>C1COCC1.O>[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH:16]=[O:17])([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc(CO)cc([N+](=O)[O-])c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of oxalylchloride (26 ml, 0.30 mol) in CH2Cl2 (600 ml) DMSO (43 ml, 0.60 mol) was added, maintaining the temperature between −50° C. and −65° C. To the reaction solution was then added 3,5-dinitrobenzyl alcohol (50g), in THF (100 ml), maintaining the temperature between −50° C. and −65° C. The reaction mixture was stirred at −65° C. for 30 minutes and then triethylamine (170 ml) was added at −50° C. and −65° C. The reaction temperature was then adjusted to room temperature and H2O (800 ml) was added. The organic phase was washed with sat. NaHCO3 (500 ml), 5 times with diluted HCl (300 ml) and finally brine. The organic phase was then dried over MgSO4 and the volatile solvents were removed at reduced pressure. The crude product was then triturated with heptane, which gave 45.8 g (89%) of 3,5-dinitrobenzaldehyde.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][N:13]([CH3:25])[C:14]([C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[CH:20][CH:21]=1)=[O:15]>>[CH3:12][N:13]([CH3:25])[C:14](=[O:15])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Reactant: CN(C)C(=O)c1cccc(B(O)O)c1
Product: Cc1cc([N+](=O)[O-])cnc1-c1cccc(C(=O)N(C)C)c1
Yield: 94 %

Procedure:
Obtained (0.620 g, yield 94%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (2.30 mmol, 0.500 g), 3-(dimethyl-carbamoyl)phenylboronic acid (2.33 mmol, 0.450 g).
Reaction SMILES: [K].[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][CH2:12][CH:13]=[CH2:14]>CO>[CH2:14]([N:5]1[CH:4]=[C:3]([Br:2])[CH:8]=[N:7][C:6]1=[O:9])[CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCBr
Reactant: O=c1ncc(Br)c[nH]1
Agent: [K]
Solvent: CO
Product: C=CCCn1cc(Br)cnc1=O
Yield: 50 %

Procedure:
A mixture of the potassium salt of 5-bromopyrimid-2-one (0.01 mol) and 4-bromo-1-butene (0.015 mol) was heated in methanol (60 ml) at 70° C. for 40 h. The reaction mixture was then evaporated and the mixture extracted with chloroform. This solution was washed with 1 N NaOH (5 ml). with water (5 ml) and dried (MgSO4) before evaporating; yield 50%, m.p. 127°-128° C. (acetone). (Found: C, 42.06; H, 3.94. Calc. for C8H9BrN2O: C, 41.94; H, 3.96).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([Mg]Br)[CH:16]=[CH2:17].P([O-])(O)(O)=O.[Na+]>C(OCC)C>[CH2:17]([C:11]1([OH:14])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]1)[CH:16]=[CH2:15]
Reactant: C=CC[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCOCC
Product: C=CCC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h

Procedure:
Into a solution of 4.98 g of 1-(tert-butoxycarbonyl)-4-piperidone in diethyl ether (150 ml) was dropped at 0° C. in a nitrogen atmosphere 30 ml of a 1.0 M solution of allylmagnesium bromide in diethyl ether and the resulting mixture was stirred for 3 hours. Then the reaction mixture was poured into an aqueous solution of sodium dihydrogenphosphate and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 4.12 g of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:8])[NH:4][CH:5]=[CH:6][CH:7]=1.C([O-])(C)(C)C.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=1[CH2:25][O:26][CH3:27].Cl>CN1CCCC1=O>[Br:1][C:2]1[C:3](=[O:8])[N:4]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][C:17]=2[CH2:25][O:26][CH3:27])[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]cccc1Br
Reactant: COCc1cc([N+](=O)[O-])ccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COCc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 44.2 g (85% purity, 216 mmol) of 3-bromopyridone in 450 ml of N-methylpyrrolidone were introduced as initial charge, and 29.1 g of potassium tert-butanolate (259 mmol) were added in portions such that the temperature remained below 30° C. The mixture was stirred for 1 h and then 40 g (216 mmol) of 1-fluoro-2-(methoxymethyl)-4-nitrobenzene were added. The reaction mixture was stirred for 4 h at 80° C., cooled to RT and stirred into an ice/water mixture. The pH was adjusted to pH=4 with semi-concentrated hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic phase was dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. The residue was dissolved in 2 l of dichloromethane, absorbed on five times the amount of silica gel and chromatographically purified on silica gel with ethyl acetate:dichloromethane 3:97 and 5:95. The product fractions were evaporated to dryness on a rotary evaporator and the residue was dried in vacuo. This gave 55 g (73%) of the desired product.