Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1)#[N:2].[CH2:15]([Mg]Br)[CH3:16].[BH4-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:2][CH:1]([C:3]1([C:8]2[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:7][CH:6]=[CH:5][CH2:4]1)[CH2:15][CH3:16]
Reactant: CC[Mg]Br
Reactant: N#CC1(c2ccc(F)cc2)CC=CC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(N)C1(c2ccc(F)cc2)CC=CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 73.2 %

Procedure:
1-cyano-1-(4-fluorophenyl)cyclopent-3-ene (117, 1.4 g, 7.48 mmol) was dissolved in toluene (3.5 mL) and ethyl magnesium bromide (5 mL, 15 mmol, 3M in ether) added. After stirring for 2.5 hours, the reaction mixture was added dropwise to ice cold methanol (50 mL), followed by sodium borohydride (560 mg, 15 mmol). The mixture was warmed to room temperature and stirred overnight. The white suspension was treated with sodium hydroxide solution (aq, 1M, 125 mL) and then extracted with dichloromethane/isopropanol (3/1). The organic phase was washed with brine, dried over sodium sulphate and evaporated to give 1.2 g of a yellow oil. This was taken up in dichloromethane and extracted twice with dilute hydrochloric acid (2M). The combined aqueous layers were made basic with aqueous sodium hydroxide solution (5M) and re-extracted with dichloromethane/isopropanol (3/1). Drying over sodium sulphate and evaporation gave 348 mg of the desired product Rt=2.37 min (Method 2). Detected mass: 220.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:37])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21](S(C5C=CC=CC=5)(=O)=O)[CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:38])[C:5]([C:39]([OH:41])=[O:40])=[CH:4]1)[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:37])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([C:19]4[C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[NH:21][CH:20]=4)[CH2:14]3)[CH:11]=2)[C:6](=[O:38])[C:5]([C:39]([OH:41])=[O:40])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cn(S(=O)(=O)c5ccccc5)c5ccccc45)C3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4c[nH]c5ccccc45)C3)cc21
Yield: 64.5 %

Procedure:
A mixture of 574 mg of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-[3-[1-(phenylsulfonyl)-1H-indol-3-yl]-1-piperazinyl]-3-quinolinecarboxylic acid, 10 ml of 1N sodium hydroxide and 20 ml of dioxane was reacted as described in Example 56, giving 280 mg of the desired product, mp 230° C.
Reaction SMILES: C[N:2](C)[C:3]1[NH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[N:7]=1>CO.N>[NH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[N:7]=1
Reactant: CN(C)c1nc(-c2c[nH]c3ccccc23)c[nH]1
Agent: N
Solvent: CO
Product: Nc1nc(-c2c[nH]c3ccccc23)c[nH]1

Procedure:
Referring to FIG. 6, similarly, treatment of 2-amino-4-(3-indolyl)imidazole 6 under analogous MeOH—NH3 conditions in air produced fused pentacyclic dimer 9 as a dark-violet to black solid. Upon further standing in MeOH—NH3, dimer 9 underwent aminolysis to afford imine 10. Hydrolysis of the imine functionality of imine 10 gave N,N-didesmethylgrossularine-1 2. Alternatively, N,N-didesmethylgrossularine-1 2 can be obtained directly from the hydrolysis of dimer 9. All spectral data of synthetic N,N-didesmethylgrossularine-1 2 were in excellent agreement with those reported for the natural product.[2] In noting differences between dimethylaminoimidazole 5 and its didesmethyl amino analog 6, the precyclized desmethylamino dimer corresponding to dimer 7 was not obtained in the case of 2-amino-4-(3-indolyl)imidazole 6. This outcome is attributed to the greater solubility of the putative desmethyl intermediate in methanolic ammonia. In the case of 2-dimethylamino-4-(3-indolyl)imidazole 5, N,N-dimethylamino analog 7c corresponding to dimer 9 also was not obtained. The greater propensity towards aminolysis of this putative guanidinium ion intermediate accounts for this result.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:30]12[CH2:38][CH2:37][CH:34]([CH2:35][CH2:36]1)[NH:33][CH2:32][CH2:31]2>>[CH3:28][N:26]([CH3:27])[C:25]([C:7]1[N:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:10]2[N:11]=[C:12]([NH:15][C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:33]4[CH:34]5[CH2:37][CH2:38][N:30]([CH2:36][CH2:35]5)[CH2:31][CH2:32]4)=[O:21])=[CH:18][N:17]=3)[N:13]=[CH:14][C:9]=2[CH:8]=1)=[O:29]
Reactant: C1CN2CCC(CC2)N1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCN5CCC4CC5)cn3)nc2n1C1CCCC1
Yield: 25.1 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (120 mg, 0.198 mmol, 1.0 eq) was combined with 1,4-Diaza-bicyclo[3.2.2]nonane (43.3 mg, 0.218 mmol, 1.1 eq) which gave 7-cyclopentyl-2-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (25 mg) in 23% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm 1.64-1.81 (m, 2H) 1.86 (br. s., 2H) 2.00-2.22 (m, 6H) 2.51-2.70 (m, 2H) 3.03-3.16 (m, 5H) 3.18 (s, 7H) 3.79 (br. s., 2H) 4.83 (quin, J=8.84 Hz, 1H) 6.50 (s, 1H) 7.81 (dd, J=8.84, 2.27 Hz, 1H) 8.35-8.44 (m, 2H) 8.58 (d, J=8.59 Hz, 1H) 8.79 (s, 1H). HRMS m/z, (M+H)+: 503.2891
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][Li]>O1CCCC1.CCOCC>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][N:9]=1
Reactant: [Li]C
Reactant: c1ccc(-c2cccnc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 21.3 %

Procedure:
A solution of 3-(phenyl)pyridine (1.55 g, 10 mmol) in tetrahydrofuran (10 ml) was stirred at −78° C. and treated with methyllithium (1.4 M, 7.5 mL, 10 mmol) in ether. The resulting yellow solution was stirred for 1 h, allowed to warm to 0° C., stirred 1 h, quenched with saturated ammonium chloride, and extracted with ether. The combined organic phase was washed with water and with brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed (silica gel, 25% ethyl acetate/hexane) to give the title compound (0.36 g).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1>Br.C(O)(=O)C.O>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[N:15][N:7]3[C:6](=[O:19])[C:5]=2[CH:4]=1
Reactant: COc1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2[nH]c3ccc(O)cc3c(=O)n2n1

Procedure:
A suspension of 4,9-dihydro-7-methoxy-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid (2.0 g; 0.0077 mole) in 48% hydrobromic acid (30 ml) and glacial acetic acid (50 ml) is refluxed for 23 hrs. The mixture is cooled and then diluted with water (25 ml). The product, which precipitates out, is collected by filtration and recrystallized from DMF-Ether (1:1, 90 ml). Yield 1.1 g; mp 285°-286° C. (d).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][NH:20][CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1.[CH3:29][N:30]([CH3:35])[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl.N1C=CC=CC=1.C(N(C(C)C)CC)(C)C>[Cl:2][C:3]1[C:4]([F:28])=[C:5]([CH:25]=[CH:26][CH:27]=1)[NH:6][C:7]1[C:16]2[C:11](=[CH:12][C:13]([O:23][CH3:24])=[C:14]([O:17][C@H:18]3[CH2:22][CH2:21][N:20]([S:31](=[O:33])(=[O:32])[N:30]([CH3:35])[CH3:29])[CH2:19]3)[CH:15]=2)[N:10]=[CH:9][N:8]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCNC1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(S(=O)(=O)N(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.5 %

Procedure:
4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-pyrrolidin-3-yloxy]quinazoline hydrochloride (0.21 g, 0.49 mmole; prepared as described in Example 30-preparation of starting materials) was dissolved in a mixture of methylene chloride (4 ml), pyridine (1 ml) and di-isopropylethyl amine (0.17 ml) under a nitrogen atmosphere. Dimethylsulfamoyl chloride (0.08 ml, 0.75 mmole) was added to the stirred solution. After stirring overnight at ambient temperature, the reaction mixture was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia)(98/2). The fractions containing the expected product were evaporated under vacuum and the residual gum was triturated with diethylether and evaporated to give the title product as a dry foam (0.13 g; 53%); 1H NMR Spectrum: (DMSO d6) 2.16-2.21 (m, 1H); 2.25-2.38 (m, 1H); 2.76 (s, 6H); 3.41-3.50 (m, 3H); 3.71 (dd, 1H); 3.93 (m, 3H); 5.18 (m, 1H); 7.15-7.35 (m, 2H); 7.44-7.55 (m, 2H); 7.78 (s, 1H); 8.37 (s, 1H); 9.59 (s, 1H); Mass Spectrum: (M+H) 496.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:31]([C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1)#[N:32].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:30]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:37]3[CH:38]=[C:33]([CH:34]=[CH:35][CH:36]=3)[C:31]#[N:32])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(C#N)c2)CC1
Yield: 16 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless solid (16%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:9]([O:22][CH3:23])=[C:10]([C:15]([O:20][CH3:21])=[C:16]([F:19])[C:17]=1[CH3:18])[C:11](OC)=[O:12].[H-].Cl>C(OCC)C.O.C(OCC)(=O)C>[F:7][C:8]1[C:9]([O:22][CH3:23])=[C:10]([C:15]([O:20][CH3:21])=[C:16]([F:19])[C:17]=1[CH3:18])[CH2:11][OH:12]
Reactant: COC(=O)c1c(OC)c(F)c(C)c(F)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COc1c(F)c(C)c(F)c(OC)c1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Lithium aluminium hydride (0.124 g) was added in a single portion to a solution of methyl 3,5-difluoro-2,6-dimethoxy-4-methylbenzoate (0.754 g) in dry diethyl ether (15 cm3) and the mixture stirred for one hour at the ambient temperature. Ethyl acetate was then added to decompose any remaining hydride, after which water was added and the mixture acidified with dilute hydrochloric acid. After extracting the mixture with diethyl ether, the extracts were dried over anhydrous magnesium sulphate and then concentrated by removal of the solvent by evaporation under reduced pressure to yield 3,5-difluoro-2,6-dimethoxy-4-methylbenzyl alcohol (0.66 g) which solidified on standing (mp. 80°-81° C.).
Reaction SMILES: FC1(F)CC1CN1CCN(C2SC(C(OCC)=O)=C(C)N=2)C1=O.[F:24][C:25]1([F:46])[CH2:27][CH:26]1[CH2:28][N:29]1[C:33](=[O:34])[N:32]([C:35]2[S:36][C:37]([C:41]([O:43]CC)=[O:42])=[C:38]([CH3:40])[N:39]=2)[CH:31]=[N:30]1>>[F:46][C:25]1([F:24])[CH2:27][CH:26]1[CH2:28][N:29]1[C:33](=[O:34])[N:32]([C:35]2[S:36][C:37]([C:41]([OH:43])=[O:42])=[C:38]([CH3:40])[N:39]=2)[CH:31]=[N:30]1
Reactant: CCOC(=O)c1sc(-n2cnn(CC3CC3(F)F)c2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(CC3CC3(F)F)C2=O)nc1C
Product: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(=O)O
Yield: 18 %

Procedure:
Following the procedure as describe in Preparation 14, making variations as required to replace ethyl 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-((2,2-difluorocyclopropyl)methyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colourless solid in 18% yield: mp 220-222° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.59 (br, 1H), 7.35 (dd, J=13.9, 7.7 Hz, 1H), 7.17 (d, J=7.7 Hz, 1H), 7.07 (dd, J=18.9, 9.0 Hz, 2H), 5.14 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.9 (d), 153.2, 136.3 (d), 130.7 (d), 123.9 (d), 115.8 (d), 115.3 (d), 47.7 (d); MS (ES+) m/z 317.1 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:21][C:22]1[S:23][C:24]([CH2:27]Cl)=[CH:25][CH:26]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[N:14]([CH2:27][C:24]3[S:23][C:22]([Cl:21])=[CH:26][CH:25]=3)[CH:13]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cnccc23)CC1
Reactant: ClCc1ccc(Cl)s1
Product: CCOC(=O)N1CCC(c2cn(Cc3ccc(Cl)s3)c3cnccc23)CC1
Yield: 59.7 %

Procedure:
This compound was prepared following the procedure described in example 24, part C, starting with 8.7 g (31.8 mmol) of 4-(1H-pyrrolo[2,3-c]pyridin-3-yl)-piperidine-1-carboxylic acid ethyl ester and 5.75 ml (47.7 mmol) of 2-chloro-5-chloromethylthiophen. After standard work-up and purification, 7.67 g (60% of yield) of 4-[1-(5-chlorothiophen-2-ylmethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[N+:18]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(O)C.[Zn]>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:15]2[CH2:17][C@H:16]2[NH2:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Zn]
Solvent: CC(C)O
Product: N[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Yield: 69.6 %

Procedure:
Zn dust (1.97 g, 30 mol) was added in small portions, over a period of 30 min, to a vigorously stirred solution of 1-(benzyloxy)-4-[(1R,2S)-2-nitrocyclopropyl]benzene (Intermediate A, 0.81 g, 3.0 mmol) in i-PrOH (25 mL) and HCl (11 mL of aqueous solution 2.7 N, 30 mmol). After 17 h the mixture was filtered through a pad of celite, that was washed with 10 mL of methanol. The filtrate was concentrated and 10 mL of water were added, washing with CH2Cl2 (3×15 mL). The organic layers were dried over anhydrous Na2SO4 and filtered. After removal of the solvent, the crude product was purified by column chromatography on silica gel (10% MeOH/CH2Cl2) affording 0.50 g of (trans)-2-[4-(benzyloxy)phenyl]cyclopropanamine [Rf=0.2 (10% MeOH/CH2Cl2), white solid, 70% yield].
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[NH:5][C:4](=[O:16])[C:3]=1[N:17]=O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>N>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[O:15])[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]=1[NH2:1]
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1Cc1ccccc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Nc1c(N)n(Cc2ccccc2)c(=O)[nH]c1=O

Procedure:
To a solution of 6-amino-5-nitroso-1-benzyl-1,3-dihydropyrimidine-2,4-dione (1.15 g, 4.7 mmol) in 12.5% aqueous ammonia (40 ml) at 70° C. was added sodium hydrosulfite (2.44 g, 14 mmol) in portions over 15 minutes. On cooling the reaction mixture in an ice bath the product precipitated out. It was filtered, washed with water, and dried under reduced pressure, to provide 5,6-diamino-1-benzyl-1,3-dihydropyrimidine-2,4-dione, a compound of formula (21).
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][C@@H:17]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(#N)C.O.C(O)(=O)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:16]2[CH2:20][CH2:19][CH2:18][C@@H:17]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]=1[CH3:12]
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: Cc1c(N2CCC[C@@H]2C(=O)OC(C)(C)C)nc2cc(F)cc(F)c2c1Cl
Temperature: 140 °C

Procedure:
The 2,4-dichloro-5,7-difluoro-3-methylquinoline (450 mg, 1.8 mmol), (R)-tert-butyl pyrrolidine-2-carboxylate (780 mg, 4.50 mmol) and triethylamine (0.63 mL, 4.5 mmol) were combined in acetonitrile (11 mL). The mixture was then heated in a microwave reactor at 140° C. for 90 min. The reaction mixture was then cond to dryness and diluted with water (35 mL) and acetic acid (3 mL) to acidify the solution. This mixture was extracted with EtOAc (1×100 mL) and DCM (1×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and dried over magnesium sulfate. The filtrate was cond to obtain (R)-tert-butyl 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)pyrrolidine-2-carboxylate. Mass Spectrum (ESI) m/e=383.2 (M+1).
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([O:7]CC)=O)(=O)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][NH:39][C:40]=1[NH2:41]>C1(C)C(C)=CC=CC=1>[C:28]1([CH3:43])[CH:33]=[C:32]([CH3:34])[CH:31]=[C:30]([CH3:35])[C:29]=1[C:36]1[C:37]([CH3:42])=[N:38][N:39]2[C:5](=[O:7])[C:4]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:1]([CH3:2])[NH:41][C:40]=12
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)Cc1c(C)[nH]c2c(-c3c(C)cc(C)cc3C)c(C)nn2c1=O
Reaction time: 3 h

Procedure:
Diethyl acetylsuccinate (0.3 mL) and a catalytic amount of 4-toluenesulfonic acid monohydrate were added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (100 mg) of Reference Example 1 in xylene (5 mL). Under heating under reflux, the mixture was stirred for three hours while distilling water off with Dean-Stark. The reaction solution was cooled, water was added thereto. The mixture was extracted twice with ethyl acetate, and washed twice with an aqeous saturated solution of sodium bicarbonate. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography, to give the title compound (200 mg) as a yellow amorphous material.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1.C([O:15][C:16]([CH:18]1[CH2:20][CH:19]1[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([Cl:28])[CH:22]=1)=[O:17])C>>[Cl:28][C:23]1[CH:22]=[C:21]([CH:19]2[CH2:20][CH:18]2[C:16]([OH:17])=[O:15])[CH:26]=[CH:25][C:24]=1[O:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]([CH3:12])[CH3:11])[N:4]=1
Reactant: CC(C)Sc1cccc(CCl)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(Cl)c1
Product: CC(C)Sc1cccc(COc2ccc(C3CC3C(=O)O)cc2Cl)n1
Yield: 58.5 %

Procedure:
2-Chloromethyl-6-isopropylsulfanyl-pyridine (40 mg, 0.19 mmol) obtained in Step C of Preparation Example 16 and 2-(3-chloro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (52 mg, 0.21 mmol) obtained in Step B of Preparation Example 47 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (42 mg, 65%).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:19][C:20]1[C:21](Cl)=[N:22][CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.[Cl-].[Na+].O>[Br:19][C:20]1[C:21]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Clc1ncccc1Br
Reactant: Cn1c(Nc2ccc(O)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1c(Nc2ccc(Oc3ncccc3Br)cc2)nc2ccccc21
Temperature: 25 °C

Procedure:
To a round bottomed flask was added 4-(1-methyl-1H-benzo[d]imidazol-2-ylamino)phenol (1.0058 g, 4.20 mmol), 3-bromo-2-chloropyridine (1.213 g, 6.31 mmol), and cesium carbonate (2.74 g, 8.41 mmol) in DMSO (14.01 mL) at 100° C. to stir. Upon completion, reaction was allowed to cool to room temperature. The reaction mixture was diluted with water (10 mL)/Brine (10 mL) and extracted with DCM (3×15 mL). A precipitate formed during extraction. The solid was filtered to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-1-methyl-1H-benzo[d]imidazol-2-amine.
Reaction SMILES: [C:1]1([CH:7]([OH:13])[CH2:8][CH2:9][C:10]#[C:11][CH3:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([O:18][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:21])=[O:20])(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(OCC)C>[F:23][C:22]([F:25])([F:24])[S:19]([O:18]/[C:11](=[C:10]1/[CH:2]([CH:1]([CH3:7])[CH3:6])[O:13][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]/1)/[CH3:12])(=[O:20])=[O:21]
Reactant: CC#CCCC(O)c1ccccc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: C/C(OS(=O)(=O)C(F)(F)F)=C1/CCC(c2ccccc2)OC1C(C)C
Reaction time: 1 h
Yield: 75 %

Procedure:
In dichloromethane (3.0 mL) were dissolved 1-phenylhex-4-yn-1-ol (0.28 mmol) and isobudylaldehyde (0.34 mmol) and the solution was cooled to −78° C. before the addition of trimethylsilyltriflate (TMSOTf) (0.86 mmol) thereto. At the same temperature, the reaction solution was stirred for 1 hour, followed by slow temperature elevation to room temperature over 3 hours. Stirring was further conducted at room temperature for an additional one to two hours in the reaction solution. After the addition of an aqueous NaHCO3 solution, the reaction solution was diluted with diethylether. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The purification of the concentrate through column chromatography afforded the title compound (Yield 75%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH2:21][OH:22])[O:12]1.N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([O:22][CH2:21][C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:19])([CH3:20])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)(=[O:31])[CH3:30]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](CO)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Yield: 100 %

Procedure:
[(3aR,4R,6R,6aR)-6-(6-Chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol (1.000 g, 0.003060 mol), pyridine (495.1 μL, 0.006121 mol), 4-dimethylaminopyridine (0.0748 g, 0.000612 mol) and acetic anhydride (577.5 μL, 0.006121 mol) were stirred in methylene chloride (20 mL) at room temperature for 1 h. The solution was diluted with Methylene chloride, extracted with HCl 1N, dried over NA2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/DCM 0% to 25%) to obtain the product (1.129 g, 84%) as an oil.