Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[O:18])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH3:28][N:29]([CH3:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)=[O:18])[CH2:13][CH2:12]2)=[C:7]2[N:8]=[C:34]([C:33]3[CH:36]=[CH:37][C:30]([N:29]([CH3:38])[CH3:28])=[CH:31][CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cc1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc4[nH]c(-c5ccc(N(C)C)cc5)nc34)CC2)cc1
Temperature: 70 °C

Procedure:
To a mixture of (4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)(4-methoxyphenyl)methanone (0.034 g, 0.09 mmol), ethanol (3 ml), and 4-dimethylamino-benzaldehyde (0.018 g, 0.12 mmol) was added a freshly prepared aqueous solution of Na2S2O4 (1M; 0.35 ml, 0.35 mmol). The reaction mixture was heated at 70° C. for 5 h, then allowed to cool to room temperature and the solvents were removed in vacuo. The residue was absorbed on silica gel and the free running powder was placed on a 10 g isolute silica column, which was eluted first with ethyl acetate/dichloromethane (v/v; 6:4) and then 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was isolated as a pale yellow solid after trituration with diethyl ether (0.008 g, 20%); 1H-NMR (500 Mz, DMSO-d6) 3.00 (s, 6H, N(CH3)2), 3.68 (br s), and 3.72 (br s) (8H, piperazine N(CH2)2), 3.81 (s, 3H, OCH3), 6.82 (d, J=8.93 Hz, 2H), and 8.01 (d, J=8.85 Hz, 2H) (2,6-C6H4—NMe2 and 3,5-C6H4—NMe2), 7.02 (d, J=8.64 Hz, 2H) and 7.45 (d, J=8.62 Hz, 2H) (2,6-C6H4—OMe and 3,5-C6H4—OMe), 8.06 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.15 (s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH:1]1([C:5]([NH2:7])=[NH:6])[CH2:4][CH2:3][CH2:2]1.[C:8]([OH:16])(=[O:15])/[C:9](=[C:11](\[CH:13]=O)/[Br:12])/Br>>[Br:12][C:11]1[C:9]([C:8]([OH:16])=[O:15])=[N:6][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:7][CH:13]=1
Reactant: N=C(N)C1CCC1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Product: O=C(O)c1nc(C2CCC2)ncc1Br

Procedure:
The product was obtained starting from cyclobutanecarboxamidine (200 mg, 1.5 mmol) and mucobromic acid (180 mg, 0.7 mmol) according to the method described in intermediate A-4, step 1 as light brown solid (38 mg, 21%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[C:38]([C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1)#[N:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([C:38]#[N:39])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(C#N)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120-(1) and 3-cyanophenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 637 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-cyanophenyl)-2-thienylmethyl)-4-methylbenzene was used and treated in a manner similar to Example 106-(3) to give the target compound as colorless powder. APCI-Mass m/Z 469 (M+NH4).
Reaction SMILES: Br[C:2]1[C:3]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:4][N:5]2[C:10]([NH:11][CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)=[N:9][C:8]([S:17][CH3:18])=[N:7][C:6]=12.C(=O)([O-])[O-].[Na+].[Na+].[F:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.C(OCC)(=O)C>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:12]1([NH:11][C:10]2[N:5]3[N:4]=[C:3]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:2]([C:36]4[CH:35]=[CH:34][N:33]=[C:32]([F:31])[CH:37]=4)=[C:6]3[N:7]=[C:8]([S:17][CH3:18])[N:9]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(Br)c2n1
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1nc(NC2CCCC2)n2nc(-c3ccccc3)c(-c3ccnc(F)c3)c2n1
Temperature: 100 °C
Yield: 33.3 %

Procedure:
8—Bromo-N-cyclopentyl-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine (0.20 g, 0.50 mmol) was dissolved in N,N-dimthylformamide. To this solution was added dichlorobis(triphenylphosphine)palladium (II] (70 mg, 0.2 equiv), anhydrous sodium carbonate (105 mg, 2 equiv), 2-fluoro-4-pyridinylboronic acid (91 mg, 1.3 equiv) and a few drops of water. The reaction mixture was heated at 100° C. for 12 hours, at which time no starting material remained in the reaction mixture. Ethyl acetate and water were added to the reaction mixture. The phases were separated and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate:hexane 1:1) gave 70 mg (33%) of N-cyclopentyl-8-(2-fluoro-4pyridinyl)-2-(methylsulfanyl)-7-phenylpyrazolo[1,5-a][1,3,5]triazin-4-amine as a white foam. 1H-NMR (CDCl3): δ 8.10 (d, 1H), 7.60 (m, 2H), 7.52 (m, 3H), 7.37 (m, 1H), 7.29 (s, 1H), 6.55 (d, 1H), 4.63 (m, 1H), 2.66 (s, 3H), 2.3–2.1 (m, 2H), 2.0–1.6 (m, 6H);F-NMR (CDCl3): δ −69.01; MS m/z 421 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[CH2:29]([N:36]([CH2:38][C:39]1[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=1)[CH3:37])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([N:36]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([NH:43]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:44][CH:45]=1)[CH3:37])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CN(Cc1ccccc1)Cc1ccc(N)cc1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(C)Cc2ccccc2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-benzyl-N-methyl-aminomethyl)-aniline Rf value: 0.4 (silica gel, methylene chloride/ethanol=10:1) C33H31N3O3
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[NH2:7]
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cnccc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
An ice-cold solution of [4-(2-chloro-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester (1.08 g, 3.54 mmol) in CH2Cl2 (11 mL) was treated with TFA (4.04 g, 2.73 mL) and stirred at room temperature for 3.5 hours. The volatiles were removed at a rotary evaporator and the residue taken up in CH2Cl2 and saturated aqueous NaHCO3 solution and the layers were separated. The aqueous layer was extracted twice with CH2Cl2 and the organic layers were washed with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (0.658 g, 90%). MS (ESI): m/z=205.05 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and Cul (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([C:8]([Cl:13])=[O:10])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ncccc1F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncccc1F
Temperature: 25 °C
Yield: 98.2 %

Procedure:
A suspension of 3-fluoropicolinic acid (4.23 g, 30 mmol) and thionyl chloride (35.7 g, 21.9 ml, 300 mmol) was heated to reflux for 15 h at which time it became a dark brown solution. Then, the heating was stopped and the reaction mixture was allowed to cool to room temperature and it was diluted with toluene. Then, the solvent and excess thionyl chloride were removed under vacuum. The residue was azeotrophed one more time with toluene and the resulting brown residue was dried under high vacuum to obtain 3-fluoropicolinoyl chloride (30) (4.70 g, 98.2% yield) as a brown paste which was used directly in the next step.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][CH:18]=[CH:19][CH:20]=1.[C:22](=O)([O-])[O-:23].[Na+].[Na+]>CN(C)C=O>[CH3:6][O:7][C:8](=[O:21])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:17][C:18]([CH:22]=[O:23])=[CH:19][CH:20]=1
Reactant: COC(=O)CCCCCCCc1ccco1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)CCCCCCCc1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
6.13 g of phosphorous oxychloride were added, while stirring, to 2.93 g of dimethyl formamide at 5°-10° C for 5 minutes. The mixture was kept at 0°-5° C for 40 minutes and then heated to room temperature. Immediately, and with vigorous stirring, 8.96 g of 8-(2-furyl)-octanoic acid methyl ester were added, whereupon the mixture was cooled to 5°-10° C in an ice-salt bath during 1 hour. After further 1 hour at room temperature, 40 g of ice were added, whereupon the mixture was neutralized with 10 g of sodium carbonate. The two phases were then separated, and the aqueous phase was extracted with ether. The combined organic phases were dried and then distilled. Boiling point 144° C at 0.2 mm Hg.
Reaction SMILES: [N:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@H:3]([OH:8])[CH2:2]2.[H-].[Na+].[N:11]([C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:18]=1)([CH3:16])[CH3:15])=[C:12]=[O:13]>C1COCC1>[N:1]12[CH2:7][C@H:4]([CH2:5][CH2:6]1)[C@H:3]([O:8][C:12](=[O:13])[NH:11][C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([CH3:25])=[CH2:24])[CH:18]=1)([CH3:16])[CH3:15])[CH2:2]2
Reactant: C=C(C)c1cccc(C(C)(C)N=C=O)c1
Reactant: O[C@@H]1CN2CC[C@H]1C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)c1cccc(C(C)(C)NC(=O)O[C@@H]2CN3CC[C@H]2C3)c1
Reaction time: 0.25 h
Yield: 25.7 %

Procedure:
To a solution of (+/−)-(3S,4S)-1-azabicyclo[2.2.1]heptan-3-ol (294 mg, 2.6 mmol) in THF (5 mL) at room temperature was added NaH [60%, oil] (107 mg, 2.67 mmol). The reaction mixture was stirred for 15 min and 1-(2-isocyanatopropan-2-yl)-3-(prop-1-en-2-yl)benzene (344 uL, 1.73 mmol) was added dropwise. The reaction was stirred for a period of 30 min and quenched with brine. The solution was extracted with EtOAc and the organic layer was dried over Na2SO4 and concentrated. The crude material was purified on a combiflash (SiO2 cartridge, CHCl3 and 2N NH3 in MeOH) to afford the corresponding carbamate as a clear oil (140 mg, 26%). 1H NMR (400 MHz, CDCl3) δ 7.26-7.20 (m, 3H), 7.11 (m, 1H), 5.18 (s, 1H), 5.19 (br s, 1H), 5.01 (s, 1H), 4.81 (br s, 1H), 2.99 (br s, 1H), 2.82(br s, 1H), 2.70 (br s, 1H), 2.53 (br s, 2H), 2.33 (br s, 1H), 2.02 (s, 3H), 1.76 (br s, 1H) 1.61 (br s, 6H), 1.52 (br s, 1H), 1.37 (br s, 1H) ppm. 13C NMR (100 MHz, CDCl3) δ 147.1, 143.7, 141.5, 128.5, 124.1, 122.1, 112.7, 75.6, 60.6, 59.4, 55.4, 54.3, 53.9, 41.5, 29.9, 29.8, 29.4, 22.2, 21.6 ppm. Purity: >98% UPLCMS (210 nm); retention time 0.83 min; (M+1) 315
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:15]1([CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[OH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:15]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1
Reactant: Oc1ccc(O)cc1
Reactant: ClCCCCCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 10 g of 2-(6-chlorohexyloxy)tetrahydropyrane, 25 g of hydroquinone, 31 g of potassiumcarbonate, 0.752 g of potassiumiodide and 250 ml of dimethylsulfoxide was allowed to react for 4 days at 80° C. Subsequently, the reaction mixture was cooled to room temperature and after addition of water extracted with ether. The organic phase was then dried over sodium sulphate, filtered and concentrated to dryness. Chromatography on silica with 10% ethylacetate in toluene gave 11 g of product as a yellowish oil.
Reaction SMILES: Br[C:2]1[C:3]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:7]=1[N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C.C([Sn](CCCC)(CCCC)[C:49]([O:51]CC)=[CH2:50])CCC>O1CCOCC1.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>[NH2:8][C:7]1[N:6]2[N:25]=[CH:26][C:27]([C:28]3[CH:29]=[N:30][C:31]4[C:36]([CH:37]=3)=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:5]2[N:4]=[C:3]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[C:2]=1[C:49](=[O:51])[CH3:50]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1c(Br)c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1c(N2CCOCC2)nc2c(-c3cnc4ccccc4c3)cnn2c1N
Temperature: 100 °C

Procedure:
A degassed mixture of 6-bromo-5-morpholino-3-(quinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (141 mg, 0.20 mmoL), tributyl(1-ethoxyvinyl)tin (112 mg, 0.31 mmoL), Pd(PPh3)4 (24 mg, 0.02 mmoL) in Dioxane (4 mL) was heated at 100° C. for 2 days. The mixture was cooled to room temperature and filtered through short plug of 10% KF/SiO2. The crude Stille coupling product obtained after concentrating the filtrate was then treated with 3 mL of 1:1 mixture of TFA and H2O at room temperature for 30 min. Concentration and purification by prep-LC afforded 1-(7-amino-5-morpholino-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-6-yl)ethanone. LCMS tR=3.32 Min. Mass calculated for, M+ 388.1, observed LC/MS m/z 389.1 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:14])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Brc1cccnc1
Product: OC(c1ccc(Br)cc1)c1cccnc1

Procedure:
Using the same protocol as described in example 22, step 1, 3-bromopyridine (482 μL, 5.0 mmol) was added to 4-bromobenzaldehyde (1.018 g, 5.5 mmol). The crude residue was chromatographed on silica gel using 1% NH4OH and 9% MeOH in dichloromethane to afford the title compound.
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
1.5 g (5.14 mmol) of ethyl[(Z)-1-(2-chloro-4-fluorophenyl)-2-cyanoethenyl]carbamate (Example 36A) and 952 mg (5.14 mmol) of 1-(propan-2-yl)piperidine-4-carbohydrazide (Example 38A) were dissolved in 27 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 3 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The resulting precipitate was filtered off, washed with a little water and then dried under high vacuum. This gave 1.25 g (61% of theory) of the product.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:9]2[O:10][C:11](=[O:18])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:17]=3[C:8]=2[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].C(N(CC)CC)C.Cl.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:38][CH:37]2[CH2:39][CH2:40][CH:34]([CH2:35][CH2:36]2)[CH2:33]1>>[ClH:29].[ClH:1].[CH:37]12[CH2:39][CH2:40][CH:34]([CH2:35][CH2:36]1)[CH2:33][N:32]([CH2:31][CH2:30][N:14]1[CH2:15][CH2:16][C:17]3[C:8]4[CH:7]=[CH:6][C:5]([O:19][CH3:20])=[C:4]([O:3][CH3:2])[C:9]=4[O:10][C:11](=[O:18])[C:12]=3[CH2:13]1)[CH2:38]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: COc1ccc2c3c(c(=O)oc2c1OC)CNCC3
Agent: Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c3c(c(=O)oc2c1OC)CN(CCN1CC2CCC(CC2)C1)CC3
Yield: 8.8 %

Procedure:
Prepared by the method described in Example 9 from 1,2,3,4-tetrahydro-7,8-dimethoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one hydrochloride (6.0 g, 0.020 moles), triethylamine (4.0 g, 0.040 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (5.4 g, 0.024 moles). Recrystallization from 95% ethanol and then from methanol yielded the product (0.85 g) as the dihydrochloride, mp 255°-258° C.
Reaction SMILES: CN(C)C=O.Br[CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]2[C:18](=[CH:19][CH:20]=1)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[NH:49][C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1>O>[O:38]1[C:42]2[CH:43]=[CH:44][C:45]([C:47]3([CH3:54])[NH:51][C:50](=[O:52])[N:49]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]4[C:13]([CH2:29][CH2:30][CH3:31])=[C:14]5[C:18](=[CH:19][CH:20]=4)[C:17]([C:25]([F:28])([F:27])[F:26])([C:21]([F:24])([F:23])[F:22])[O:16][CH2:15]5)[C:48]3=[O:53])=[CH:46][C:41]=2[O:40][CH2:39]1
Reactant: CC1(c2ccc3c(c2)OCO3)NC(=O)NC1=O
Reactant: CCCc1c(OCCCCBr)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCN2C(=O)NC(C)(c3ccc4c(c3)OCO4)C2=O)ccc2c1COC2(C(F)(F)F)C(F)(F)F
Reaction time: 8 h

Procedure:
To a N,N-Dimethylformamide (2 mL) solution of 5-(4-bromobutoxy)-4-propyl-1,1-bis(trifluoromethyl)-1,3-dihydroisobenzofuran (25 mg, 0.0557 mmol), potassium carbonate mg, 0.111 mmol) and 5-(benzo[d][1,3]dioxol-5-yl)-5-methylimidazolidine-2,4-dione (CAS: 308122-40-9:DE335993) (19.6 mg, 0.0835 mmol) were added and the mixture was stirred overnight. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by thin-layer silica-gel column chromatography (hexane:ethyl acetate=2:1) and of the title compound (30.7 mg, 92%) was obtained as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[BH4-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH:6]=[CH:7][C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC1=NN=C(C=Cc2ccc(F)cc2)c2cc3c(cc2C1)OCO3
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC1Cc2cc3c(cc2C(C=Cc2ccc(F)cc2)=NN1)OCO3
Reaction time: 2 h

Procedure:
To a mixture of 2.0 g (6.2 mmoles) of 1-(4-fluorostyryl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine prepared according to Example 86 and 10 ml of glacial acetic acid a solution of 3.0 g (79 mmoles) of sodium borohydride in 10 ml of water is added in small portions, while the temperature of the reaction mixture is kept below 35° C. The mixture is then stirred for further 2 hours and made alkaline by adding some sodium carbonate solution to it. The alkaline solution is extracted three times with 20 ml of ethyl acetate. The ethyl acetate phases are dried, evaporated and the evaporation residue is crystallized from ethanol. The crude product is purified by recrystallization from ethanol. Thus 1.39 g (69%) of substance pure on TLC is obtained. M.p.: 170-174° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>ClC(Cl)Cl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:18]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:19]
Reactant: O=C(Cl)N1CCCC1
Reactant: CNCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(CCO)C(=O)N1CCCC1
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a stirred solution of 7.5 parts of 2-(methylamino)ethanol in 75 parts of trichloromethane were added 9.8 parts of N,N-diethylethanamine while cooling in an ice bath. A solution of 13.4 parts of 1pyrrolidinecarbonyl chloride in 52.5 parts of trichloromethane was added dropwise (exothermic reaction, the temperature rose from -10° C. to ~0° C.). Upon complete addition, stirring was continued for 6 hours at room temperature. Another portion of 1.5 parts of 2-(methylamino)ethanol was added and stirring was continued over weekend at room temperature. The separated organic layer was washed with a hydrochloric acid solution 5% and water, dried, filtered and evaporated, yielding 7 parts (40.1%) of N-(2-hydroxyethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 30).