Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])([CH2:31][OH:32])[CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[C:43](OC)([CH3:45])[CH3:44].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:33]1[C:17]([CH2:16][CH2:15][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:14][CH:13]=2)([CH2:18][O:19][C:20](=[O:30])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH2:31][O:32][C:43]1([CH3:45])[CH3:44])=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)NC(CO)(CCc1ccc(OCc2ccccc2)cc1)COC(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Temperature: 95 °C
Reaction time: 6 h

Procedure:
To a solution of 2-nitro-benzoic acid 4-(4-benzyloxy-phenyl)-2-tert-butoxycarbonylamino-2-hydroxymethyl-butyl ester (105 mg, 0.19 mmol) in toluene (2 ml) is added 2,2 dimethoxypropane (0.06 ml, 0.57 mmol, 3 eq) and a catalytic amount of p-toluene sulfonic acid. The reaction mixture is stirred at 95° C. for 6 hours, then concentrated to dryness under negative pressure. 4-[2-(4-Benzyloxy-phenyl)ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxy-methyl)-oxazolidine-3-carboxylic acid tert-butyl ester is isolated as an oil (88 mg, 78%) after purification by flash chromatography (Ethyl acetate/Hexane (1/3)).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1.[CH3:17]I.[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:17])[C:7](=[O:16])[N:8]2[CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:4][N:3]=1
Reactant: CI
Reactant: CCC(CC)n1c(=O)[nH]c2cnc(Cl)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1c(=O)n(C)c2cnc(Cl)nc21
Reaction time: 1.5 h

Procedure:
To a solution of 2-Chloro-9-(1-ethyl-propyl)-7,9-dihydro-purin-8-one (100 mg, 0.41 mmol) in anhydrous DMF (2 ml) is added methyl iodide (21 ul, 0.41 mmol) followed by NaH (50%, 22 mg, 0.4571 mmol). The reaction is stirred under nitrogen for 1.5 h. The reaction mixture is quenched with ice water and extracted with EtOAc. The extracts are dried over Na2SO4 and concentrated in vacuo to give the crude 2-Chloro-9-(1-ethyl-propyl)-7-methyl-7,9-dihydro-purin-8-one. The crude product is used as is.
Reaction SMILES: C([O:5][C:6](=[O:70])[CH2:7][C@H:8]([O:62][Si:63]([CH2:68][CH3:69])([CH2:66][CH3:67])[CH2:64][CH3:65])[C:9]([CH3:61])([CH3:60])[C:10](=[O:59])[C@H:11]([CH3:58])[C@@H:12]([O:49][C:50]([O:52][CH2:53][C:54]([Cl:57])([Cl:56])[Cl:55])=[O:51])[C@@H:13]([CH3:48])[CH2:14][CH2:15][CH2:16]/[C:17](/[CH3:47])=[CH:18]\[CH2:19][C@H:20]([O:39][Si](CC)(CC)CC)/[C:21](/[CH3:38])=[CH:22]/[C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:37])([Cl:36])[Cl:35])=[O:31])[S:26][CH:27]=1)(C)(C)C.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](CC)(CC)CC)(=O)=O.Cl.P([O-])([O-])([O-])=O>C(Cl)Cl.C(OCC)(=O)C>[O:59]=[C:10]([C@H:11]([CH3:58])[C@@H:12]([O:49][C:50]([O:52][CH2:53][C:54]([Cl:55])([Cl:56])[Cl:57])=[O:51])[C@@H:13]([CH3:48])[CH2:14][CH2:15][CH2:16]/[C:17](/[CH3:47])=[CH:18]\[CH2:19][C@H:20]([OH:39])/[C:21](/[CH3:38])=[CH:22]/[C:23]1[N:24]=[C:25]([CH2:28][O:29][C:30]([O:32][CH2:33][C:34]([Cl:35])([Cl:36])[Cl:37])=[O:31])[S:26][CH:27]=1)[C:9]([CH3:61])([CH3:60])[C@@H:8]([O:62][Si:63]([CH2:68][CH3:69])([CH2:64][CH3:65])[CH2:66][CH3:67])[CH2:7][C:6]([OH:70])=[O:5]
Reactant: CC[Si](CC)(CC)O[C@@H](C/C=C(/C)CCC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Agent: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC[Si](CC)(CC)O[C@@H](CC(=O)O)C(C)(C)C(=O)[C@H](C)[C@@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)CCC/C(C)=C\C[C@H](O)/C(C)=C/c1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Reaction time: 10 h

Procedure:
A solution of tert-butyl(3S,6R,7S,8S,12Z,15S,16E)-5-oxo-3,15-bis(triethylsilyloxy)-17-(2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazol-4-yl)-4,4,6,8,12,16-hexamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-heptadeca-12,16-dienoate (2.86 g) in 12 mL of CH2Cl2 is treated with 2,6-lutidine (0.86 mL) and triethylsilyl trifluoromethanesulfonate (0.98 g) at 0° C. for 30 minutes, then at ambient temperature for 10 hours. The mixture is diluted with 50 mL of ethyl acetate and poured into 20 mL of 1 N HCl. The organic phase is separated, washed with pH 7 phosphate buffer, dried with Na2SO4, filtered, and concentrated. The residue is dissolved in 5 mL of THF and treated with 0.5 mL of 0.1 N HCl in methanol. The reaction is monitored by thin-layer chromatography, with additional aliquots of methanolic HCl being added to achieve complete reaction. When complete, the reaction is poured into 15 mL of pH 7 phosphate buffer and extracted with ethyl acetate. The extract is washed with brine, dried with Na2SO4, filtered, and evaporated. The product is purified by flash chromatography on SiO2 (1:1 hexanes/ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29](F)(F)F)[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.N[C:35]1C(C#N)=C(N2CCC(C3N(CCNC)C=C(C4C=CC(F)=C(C)C=4)N=3)CC2)N=[CH:37][N:36]=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([C:17]3[N:18]([CH2:33][CH2:35][NH:36][CH3:37])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([CH3:29])[CH:23]=4)[N:21]=3)[CH2:15][CH2:16]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CNCCn1cc(-c2ccc(F)c(C)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CNCCn1cc(-c2ccc(F)c(C)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-{4-[4-(4-fluoro-3-methyl-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=453, obsd.=453).
Reaction SMILES: [N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[N:1]([CH:4]([C:6]1[N:7]=[C:8]2[S:16][CH:15]=[C:14]([CH3:17])[N:9]2[C:10](=[O:13])[C:11]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[F:18])[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1ccccc1F
Reactant: Cc1csc2nc(C(C)N=[N+]=[N-])c(Br)c(=O)n12
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1csc2nc(C(C)N=[N+]=[N-])c(-c3ccccc3F)c(=O)n12
Temperature: 100 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a mixture of 7-(1-azidoethyl)-6-bromo-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.12 g, 0.38 mmol) and (2-fluorophenyl)boronic acid (0.064 g, 0.46 mmol) in 1,4-dioxane (4 mL) was added a 1 N solution of sodium carbonate in water (0.8 mL, 0.8 mmol) and dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (0.014 g, 0.019 mmol). The mixture was stirred at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over Na2SO4, concentrated, and purified on silica gel (0-35% ethyl acetate/hexane) to give the desired product (87 mg). LCMS calculated for C15H13FN5OS (M+H)+: m/z=330.1. Found: 330.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([C:25]5[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH:30]=5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1.[H][H]>CO.[Pd]>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)[N:12]4[C:23]([CH:25]5[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][CH2:26]5)=[N:24][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:38])[O:4][N:3]=1
Reactant: [H][H]
Reactant: Cc1noc(C)c1-c1ccc2nc(C3=CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Agent: [Pd]
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(C3CCN(C(=O)OC(C)(C)C)CC3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
(tert-Butyl 4-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (80 mg, 0.2 mmol) was dissolved in methanol (6 mL), and the mixture was degassed with nitrogen for 15 min, followed by addition of palladium on carbon (30 mg, 0.02 mmol) [Aldrich, cat. #130108]. After three vacuum/nitrogen gas refilling cycles, 1 atm hydrogen gas was charged to the mixture with a balloon. After stirring for 2 h at room temperature, the reaction mixture was filtered through Celite and the filter was subsequently washed with methanol (30 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by flash chromatography eluting ethyl acetate in hexanes (75-100%) to afford the desired product (48 mg, 60%). LCMS for C29H34O4N5 (M+H)+: calculated m/z=516.3. found 516.2; 1H NMR (400 MHz, CD3OD) δ 8.59-8.49 (m, 1H), 7.73 (m, 1H), 7.36-7.28 (m, 2H), 7.06 (d, J=8.3 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.00 (m, 1H), 4.89 (dd, J=11.7, 3.1 Hz, 1H), 4.60 (dd, J=11.6, 3.1 Hz, 1H), 4.16 (d, J=13.4 Hz, 1H), 4.04 (d, J=13.5 Hz, 1H), 2.95 (ddd, J=11.8, 8.3, 3.6 Hz, 1H), 2.88-2.51 (m, 2H), 2.25 (s, 3H), 2.11 (s, 3H), 2.06-1.94 (m, 1H), 1.92-1.66 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C)C(N(OC)C)=O)=O)(C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:16])/[CH:10]=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/[C@H](C)NC(=O)OC(C)(C)C
Agent: CON(C)C(=O)[C@@H](C)NC(=O)OC(C)(C)C
Product: COC(=O)/C=C/[C@@H](C)NC(=O)OC(C)(C)C
Yield: 79 %

Procedure:
The title compound was prepared as Methyl (2E)(4S)-4-[(tert-butoxy)carbonylamino]pent-2-enoate with (2R)-2-[(tert-butoxy)carbonylamino]-N-methoxy-N-methylpropanamide (13.05 grams, 56.18 mmol) to give the title compound (10.2 g, 79%): ES-MS (m/z) 230 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]Br.[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1cc(F)cc(F)c1
Yield: 71.8 %

Procedure:
Using 0.21 g of 3,5-difluorobenzyl bromide, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.21 g of 2-(3,5-difluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (71)).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cccc(CNc2nc(Cl)nc3sc(C(F)(F)F)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sc(C(F)(F)F)cc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH2:16]([O:24][CH2:25][CH:26]1[O:28][CH2:27]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:27][CH:26]([OH:28])[CH2:25][O:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(C)CCCCCOCC1CO1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)CCCCCOCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 68.9 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), isooctylglycidyl ether (1.9 g, 10 mmol) and ethyltriphenylphosphonium bromide (0.2 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.85 g (69%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])(C)[CH:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.Cl[C:19]1C=CC(OC)=CC=1.C1(C)C(Cl)=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:39](OCC)(=[O:46])[CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].N12CCCN=C1CCCCC2>ClC(Cl)C(Cl)Cl>[CH2:44]([O:43][C:41]([C:40]1[C:39](=[O:46])[O:17][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][C:6]=2[C:7]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=1[CH3:19])=[O:42])[CH3:45]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc(Cl)cc1
Reactant: CC1(O)C=CC(Cl)=CC1C(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)C(Cl)Cl
Solvent: Cc1ccccc1Cl
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1c(-c2ccccc2C)c2cc(Cl)ccc2oc1=O

Procedure:
A mixture of 5-Chloro-2-hydroxy-2-methylbenzophenone [prepared by reaction of 4-chloroanisole with ortho-tolyl chloride in 1,1,2,2,-tetrachloroethane in the presence of aluminum chloride (150° C., 7 hours): melting point 65°-66° C.] (71.9 g), diethyl malonate (70 ml) and 1,8diazabicyclo[5.4.0]undec-7-ene (4 ml) was stirred at 170° C. for 6 hours. The reaction mixture was purified by silica gel column chromatography (hexane) to yield 6-chloro-4-(2-methylphenyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid ethyl ester as colorless crystals (73.2 g).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([O:21]C)=[O:20])(=[O:12])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>O1CCCC1.CO>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([S:10]([NH:13][C:14]3[CH:18]=[CH:17][S:16][C:15]=3[C:19]([OH:21])=[O:20])(=[O:11])=[O:12])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1sccc1NS(=O)(=O)c1ccc2c(c1)CCC2
Temperature: 80 °C
Yield: 100.8 %

Procedure:
To a solution of 125 (0.30 g; 0.89 mmol) in tetrahydrofuran (20 mL) and methanol (7 mL) was added aqueous sodium hydroxide (20 mL; 2N) and then heated at 80° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and then extracted with diethyl ether (20 mL). The aqueous layer was separated and acidified with aqueous hydrochloric acid (15 mL; 2N) then extracted with ethyl acetate (2×20 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title product as an off-white solid (0.29 g).
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]3[NH:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[N:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)C=O.[H-].[Na+].Cl[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1>O>[F:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][N:19]2[C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=[C:15]2[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: c1ccc(CN2CCC(Cc3nc4ccccc4[nH]3)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ccccc32)cc1
Reaction time: 1 h
Yield: 90 %

Procedure:
To a stirred mixture of 55 parts of 2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole and 450 parts of N,N-dimethylformamide were added 10.6 parts of a sodium hydride dispersion 50% and stirring was continued for 1 hour. Then there were added dropwise 26 parts of 1-(chloromethyl)-4-fluorobenzene (slightly exothermic reaction). Upon completion, stirring was continued overnight at room temperature. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The solid residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 67.6 parts (90%) of 1-[(4-fluorophenyl)methyl]-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-benzimidazole; mp. 127.5° C. (34).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([CH2:11][C@@H:12]([C@@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[OH:15])[OH:13])=[O:10]>N1C=CC=CC=1>[CH3:8][C:9]([CH2:11][C@@H:12]([C@@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[OH:15])[O:13][C:1](=[O:3])[CH3:2])=[O:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-]
Solvent: c1ccncc1
Product: CC(=O)C[C@H](OC(C)=O)[C@H](O)CN=[N+]=[N-]
Reaction time: 4 h
Yield: 60 %

Procedure:
Acetic anhydride (25 mL) was added to a solution of methyl-5-azido-2.5-dideoxy-D-ribose (6.2 g, 38 mmol) in pyridine (100 mL). After 4 hours at room temperature, the mixture was concentrated in vacuo. The residue (6 g) was purified by flash chromatography eluting with hexanethylacetate (8:2). Evaporation of the eluting solvent gave the product as an oil (4.9 g, 60% yield). NMR
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl:10][CH2:11][C:12](O)=[O:13].P(Cl)(Cl)(Cl)=O>>[CH:8]1[C:9]([C:12]([CH2:11][Cl:10])=[O:13])=[C:1]([OH:2])[C:3]([OH:4])=[C:5]([OH:6])[CH:7]=1
Reactant: O=C(O)CCl
Reactant: Oc1cccc(O)c1O
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(CCl)c1ccc(O)c(O)c1O

Procedure:
Pyrogallol is reacted with chloracetic acid in the presence of phosphorus oxychloride to form ω-chloro-2,3,4-trihydroxyacetophenone,
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.Cl[CH2:11][C:12](=O)[CH3:13]>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[CH:11][N:5]2[C:4]=1[CH:9]=[CH:8][CH:7]=[CH:6]2
Reactant: CC(=O)CCl
Reactant: COCc1ccccn1
Product: COc1c(C)cn2ccccc12

Procedure:
This compound is obtained starting with 2-(methoxymethyl)pyridine and chloroacetone, using the Tschitschibabin reaction. The product is isolated in the form of a yellow oil which crystallizes in the freezer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[N:36][CH:37]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH:37]=[N:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(C#N)nc4)ncc3O2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxa borolan-2-yl)-pyridine-2-carbonitrile following a procedure analogous to that described in Example 28. LC (method 10): tR=1.70 min; Mass spectrum (ESI+): m/z=407 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH3:19].[N:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH3:19])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:26]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:27])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: Cc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc2c(N)nc3ccccc3c2n1CCCNC(=O)N1CCOCC1
Yield: 47 %

Procedure:
Using the general method of Example 150 except that the reaction was run at 0° C., 1-(3-aminopropyl)-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine (2.0 g, 7.8 mmol) was reacted with 4-morpholinecarbonyl chloride (1.17 g, 7.8 mmol) to provide 1.35 g of N-[3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]morpholine-4-carboxamide as a white solid, m.p. 226.0-228.0° C. Analysis: Calculated for C19H24N6O2: % C, 61.94; % H, 6.57; % N, 22.81. Found: % C, 61.67; % H, 6.46; % N, 22.74.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[C:43](=O)[N:44](COCC[Si](C)(C)C)[C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20](COCC[Si](C)(C)C)[C:19]3=O)[CH:13]=[CH:14][CH:15]=1>C1COCC1.O>[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH2:17][C@@H:18]3[N:24]([CH:25]=2)[C:23](=[O:26])[C:22]2[CH:27]=[C:28]([O:70][CH3:71])[C:29]([O:31][CH2:32][CH2:33][CH2:34][O:35][C:36]4[C:67]([O:68][CH3:69])=[CH:66][C:39]5[C:40](=[O:65])[N:41]6[CH:56]=[C:55]([C:57]7[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=7)[CH2:54][C@H:42]6[CH:43]=[N:44][C:38]=5[CH:37]=4)=[CH:30][C:21]=2[N:20]=[CH:19]3)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7cccc(N)c7)C[C@H]5C=N6)cc4N=C[C@@H]3C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
A solution of superhydride (0.56 mL, 0.56 mmol, 1.0 M in THF) was added dropwise to a solution of the SEM dilactam (18)(0.271 g, 0.27 mmol) in dry THF (10 mL) at −78° C. under a nitrogen atmosphere. After 1 hr a further aliquot of superhydride solution (0.13 ml, 0.13 mmol) was added and the reaction mixture was allowed to stir for another 0.5 hr, at which time LC-MS indicated that reduction was complete. The reaction mixture was diluted with water and allowed to warm to room temperature. The reaction mixture was partitioned between chloroform and water, the layers were separated and the aqueous layer extracted with additional chloroform (emulsions). Finally the combined organic phase was washed with brine and dried over magnesium sulphate. The reduced product was dissolved in methanol, chloroform and water and allowed to stir in the presence of silica gel for 72 hours The crude product was subjected to flash column chromatography (methanol/chloroform gradient) to afford the desired imine product (150 mg, 0.21 mmol, 77%) after removal of excess eluent from selected fractions.