Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:16]#[N:17])[C:11](OCC)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C.C(N(CC)CC)C>[NH2:17][C:16]1[N:26]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]=[C:11]([OH:12])[C:10]=1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1
Reactant: CCOC(=O)C(C#N)c1ccc2c(c1)OCO2
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1c(-c2ccc3c(c2)OCO3)c(O)nn1Cc1ccccc1
Yield: 40.7 %

Procedure:
To a stirred suspension of ethyl 2-(1,3-benzodioxol-5-yl)-2-cyanoacetate (76 g) and benzylhydrazine hydrochloride (99 g) in ethanol (1300 ml), triethylamine (152 ml) was slowly added at room temperature. The solution was refluxed for two days, then concentrated under reduced pressure. To the dark residue, ethyl acetate (800 ml) and water (1000 ml) were added. The white precipitate was collected by filtration washed with water and ethyl acetate, then dried under educed pressure to give the title compound as a white solid (41 g).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[N:22][CH:23]=1)([O-:17])=[O:16].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:24][C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][N:22]=2)[CH2:29][CH2:28]1
Reactant: O=Cc1ccc([N+](=O)[O-])cn1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.2 %

Procedure:
Sodium triacetoxyborohydride (1.4 g, 6.6 mmol, 2 equiv) was added portionwise to a cold (5° C.) solution of 5-nitro-pyridine-2-carbaldehyde (Step 39.3) (0.5 g, 3.3 mmol) and N-methyl-piperazine (0.4 mL, 3.6 mmol, 1.1 equiv) in DCM (10 mL). The reaction mixture was allowed to warm to rt, stirred for 16 h, diluted with DCM and saturated solution of NaHCO3, and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 91:8:1) to provide 0.532 g of the title compound as a yellow solid: ESI-MS: 237.2 [M+H]+; TLC: Rf=0.31 (DCM/MeOH/NH3aq, 91:8:1).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:8]([N+:10]([O-:12])=[O:11])=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Nc1cc([N+](=O)[O-])c(Br)cc1F
Temperature: 0 °C
Yield: 22.6 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (58.6 g) in conc. sulfuric acid (100 ml), there was dropwise added a mixture of conc. nitric acid (25.3 g) and conc. sulfuric acid (15 ml) at a temperature of 0° to -10° C. The resultant mixture was stirred at 0°-5° C. for 1 hour, poured into ice-water and extracted with toluene. The toluene layer was washed with water and an aqueous sodium hydrogen carbonate solution and concentrated. The residue was purified by silica gel chromatography to give 16.4 g of 4-bromo-2-fluoro-5-nitroaniline. M.P., 90°-92° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[CH:9])=[O:5].[OH-].[Na+].[I:20]I.Cl>CO>[CH3:1][O:2][CH2:3][C:4]([N:6]([C:11]1[C:15]([CH3:16])=[CH:14][S:13][C:12]=1[CH3:17])[CH:7]([CH3:10])[C:8]#[C:9][I:20])=[O:5]
Reactant: II
Reactant: C#CC(C)N(C(=O)COC)c1c(C)csc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCC(=O)N(c1c(C)csc1C)C(C)C#CI

Procedure:
A mixture of 2.51 g (0.01 mol) 2-methoxy-N-(2,4-dimethylthien-3-yl)-N-(1-butin-3-yl)-acetamide, 1.3 g (0.0325 mol) NaOH and 100 ml methanol are cooled with stirring to 10°, and 2.65 g (0.01 mol) powdered iodine is then slowly added. The mixture is then stirred for 3 hours at room temperature, neutralized with methanolic HCl-solution, and the solvent evaporated to yield, after chromatography, the title compound.
Reaction SMILES: [C:1]1([C:7](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[C:1]1([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)C(=Cc1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)C(Cc1ccccc1)c1ccccc1

Procedure:
10% Palladium on charcoal (0.8 g) was added to a solution of α-phenylcinnamic acid (10.0 g, 0.0445 mol) in ethanol (200 ml). The mixture was hydrogenated at ambient temperature. The mixture was filtered through Celite, and the solvent was evaporated.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][CH:22]1[CH2:24][O:23]1>C(C(C)=O)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:21][CH:22]2[O:23][CH2:24]2)=[C:7]([CH3:13])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: CC(=O)Oc1cc(C)c(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)Oc1cc(C)c(OCC2CO2)cc1C

Procedure:
Using 3.25 g of 4-acetoxy-2,5-dimethylphenol, 2.49 g of anhydrous potassium carbonate, 2.8 ml of chloromethyloxirane and 50 ml of methyl ethyl ketone, reaction and workup carried out as in Example 1-A gave about 2.97 g of 1-(4-acetoxy-2,5-dimethylphenoxy)-2,3-epoxypropane as yellow oil. Using the epoxy compound thus obtained, 2.66 g of 1-(2-methoxyphenyl)piperazine and 100 ml of dioxane, reaction and workup were carried out as in Examples 1-A and 4. After hydrolysis, workup and then conversion to hydrochloride with 2N HCl, recrystallization from methanol-acetone gave 0.80 g of white crystals, m.p. 214-215° C. (decomp.).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][C@H:12]([CH3:14])[O:11][C@H:10]([CH3:15])[CH2:9]2)=[N:6][CH:7]=1.[CH3:16][N:17]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=1)[C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH3:15][C@H:10]1[O:11][C@@H:12]([CH3:14])[CH2:13][N:8]([C:5]2[N:4]=[CH:3][C:2]([C:32]3[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=3)[CH2:29][N:17]([CH3:16])[C:18](=[O:28])[CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:7][N:6]=2)[CH2:9]1
Reactant: CN(Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1)C(=O)CNC(=O)OC(C)(C)C
Reactant: C[C@@H]1CN(c2ncc(Br)cn2)C[C@H](C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1CN(c2ncc(-c3cccc(CN(C)C(=O)CNC(=O)OC(C)(C)C)c3)cn2)C[C@H](C)O1
Temperature: 80 °C
Reaction time: 24 h
Yield: 93.5 %

Procedure:
rel-(2R,6S)-4-(5-Bromopyrimidin-2-yl)-2,6-dimethylmorpholine (118 mg) and tert-butyl (2-{methyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]amino}-2-oxoethyl)carbamate (175 mg) were dissolved in DME (2 ml) and water (1 ml), and tetrakis(triphenylphosphine)palladium (15 mg) and sodium carbonate (137 mg) were added thereto, followed by stirring at 80° C. for 24 hours. The obtained residue was subjected to liquid separation with CHCl3 and water. The organic layer was separated, and then the aqueous layer was extracted with CHCl3 again. These organic layers were combined, dried over Na2SO4, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (2% MeOH/CHCl3) to obtain tert-butyl rel-{2-[(3-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]pyrimidin-5-yl}benzyl)(methyl)amino]-2-oxoethyl]carbamate (190 mg) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=2)O1>>[CH:13]1([C:9]2[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6](=[O:20])[N:5]3[C:10]=2[C:11]([CH3:12])=[C:2]([C:29]2[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[O:37])=[CH:31][CH:30]=2)[CH:3]=[CH:4]3)[CH2:15][CH2:14]1
Reactant: CC1(C)OB(c2ccc(NC(N)=O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC(N)=O)cc3)ccn2c1=O
Yield: 28.5 %

Procedure:
Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-urea (84 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuo to afford the title compound as a yellow solid (29 mg, 26%). ESI-MS m/z: 392 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([C:11]([OH:13])=O)[CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>>[NH:20]1[C:19]([NH:18][C:11]([C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([CH3:10])[N:7]=2)=[O:13])=[N:23][N:22]=[N:21]1
Reactant: Cc1cc([N+](=O)[O-])cc(C(=O)O)n1
Reactant: Nc1nnn[nH]1
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])cc(C(=O)Nc2nnn[nH]2)n1
Yield: 40.1 %

Procedure:
1.44 g of 4-nitro-6-methyl-2-pyridinecarboxylic acid, 27 ml of thionyl chloride and 0.79 g of 5-aminotetrazole are treated in the same manner as described in Example 1. The crude product thus obtained is washed with ethanol, whereby 0.79 g of N-(5-tetrazolyl)-4-nitro-6-methyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1B(O)O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:36])[C:28]1[CH:33]=[C:32](I)[CH:31]=[CH:30][C:29]=1[NH2:35])[CH3:25]>>[CH2:24]([O:26][C:27](=[O:36])[C:28]1[C:29]([NH2:35])=[CH:30][CH:31]=[C:32]([C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:33]=1)[CH3:25]
Reactant: Cc1ccc(OCc2ccccc2)c(C2=C(B(O)O)CCC2)c1
Reactant: CCOC(=O)c1cc(I)ccc1N
Product: CCOC(=O)c1cc(C2=C(c3cc(C)ccc3OCc3ccccc3)CCC2)ccc1N

Procedure:
Prepared by general procedure C(iii) but using 2-(2-benzyloxy-5-methylphenyl)cyclopentene-1-boronic acid instead of 2-(2-benzyloxy-5-chlorophenyl)cyclopentene-1-boronic acid and 2-amino-5-iodobenzoic acid ethyl ester instead of 2-chloropyrimidine-4-carboxylic acid methyl ester.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([O:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([C@@H:30]2[CH2:34][C@H:33]([S:35]CC3C=CC(OC)=CC=3)[CH2:32][N:31]2[C:45]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][C:52]([N+:55]([O-:57])=[O:56])=[CH:51][CH:50]=2)=[O:46])=[O:29])[CH2:24][CH2:23]1)(=[O:18])[NH2:17]>C1(OC)C=CC=CC=1>[F:8][C:9]([F:15])([F:14])[S:10]([OH:13])(=[O:12])=[O:11].[C:16]([O:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]([C@@H:30]2[CH2:34][C@H:33]([SH:35])[CH2:32][N:31]2[C:45]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][C:52]([N+:55]([O-:57])=[O:56])=[CH:53][CH:54]=2)=[O:46])=[O:29])[CH2:26][CH2:27]1)(=[O:18])[NH2:17]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(CCOC(N)=O)CC3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
2.67 ml of trifluoroacetic acid and 122 μl of trifluoromethanesulfonic acid were added, whilst ice-cooling, to a solution of 417 mg of (2S,4S)-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-4-(4-methoxybenzylthio)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 9) in 753 μl of anisole, and the resulting mixture was stirred at the same temperature for 1 hour. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was washed with diethyl ether by repeated decantation and dried under reduced pressure to give 325 mg of the title compound, as a powder.
Reaction SMILES: [CH2:1]([N:3]1[C:8]2[CH:9]=[C:10]([N:13](OC)[CH3:14])[N:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([N+:24]([O-])=O)[CH:18]=2)[C:4]1=[O:27])[CH3:2].[H][H]>CO.[Pd]>[NH2:24][C:19]1[CH:18]=[C:17]([N:5]2[CH2:6][C:7]3[CH:12]=[N:11][C:10]([NH:13][CH3:14])=[CH:9][C:8]=3[N:3]([CH2:1][CH3:2])[C:4]2=[O:27])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: CCN1C(=O)N(c2ccc(F)c([N+](=O)[O-])c2)Cc2cnc(N(C)OC)cc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCN1C(=O)N(c2ccc(F)c(N)c2)Cc2cnc(NC)cc21
Yield: 84.6 %

Procedure:
1-Ethyl-3-(4-fluoro-3-nitrophenyl)-7-(methoxy(methyl)amino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (4.6 g, 12 mmol), Pd/C (0.5 g) and hydrogen (45 psi) were reacted in MeOH (100 mL) at 50° C. overnight to give 3-(3-amino-4-fluorophenyl)-1-ethyl-7-(methylamino)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one (3.2 g, 84%). 1H-NMR (400 MHz, DMSO-d6): δ 7.70 (s, 1 H), 6.94 (dd, J=11.2, 8.8 Hz, 1 H), 6.67 (dd, J=8.0, 2.4 Hz, 1 H), 6.42 (m, 1 H), 6.33 (m, 1 H), 5.98 (s, 1 H), 5.14 (s, 2 H), 4.48 (s, 2 H), 3.74 (q, J=7.2 Hz, 2 H), 2.73 (d, J=5.2 Hz, 3 H), 1.15 (t, J=7.2 Hz, 3 H); MS (ESI) m/z: 316.2 [M+H]+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]([C:28]1[S:29][C:30]([CH3:36])=[C:31]([C:33]([OH:35])=O)[N:32]=1)([CH3:27])[CH3:26].[O:37]1[C:42]2([CH2:47][CH2:46][N:45]([CH2:48][C:49]3[C:50]([F:58])=[C:51]([CH2:55][CH2:56][OH:57])[CH:52]=[CH:53][CH:54]=3)[CH2:44][CH2:43]2)[CH2:41][NH:40][CH2:39][CH2:38]1.C(N(CC)CC)C>CN(C=O)C>[F:58][C:50]1[C:51]([CH2:55][CH2:56][OH:57])=[CH:52][CH:53]=[CH:54][C:49]=1[CH2:48][N:45]1[CH2:46][CH2:47][C:42]2([O:37][CH2:38][CH2:39][N:40]([C:33]([C:31]3[N:32]=[C:28]([CH:25]([CH3:26])[CH3:27])[S:29][C:30]=3[CH3:36])=[O:35])[CH2:41]2)[CH2:43][CH2:44]1
Reactant: Cc1sc(C(C)C)nc1C(=O)O
Reactant: OCCc1cccc(CN2CCC3(CC2)CNCCO3)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1sc(C(C)C)nc1C(=O)N1CCOC2(CCN(Cc3cccc(CCO)c3F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
HATU (0.175 g) was added in one portion to a stirred solution at 0° C. of 2-isopropyl-5-methylthiazole-4-carboxylic acid (example 69, step b) (0.066 mg) and 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-ylmethyl)-2-fluorophenyl)ethanol (example 67, step f) (0.109 g) and triethylamine (0.148 mL) in DMF (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure to afford the subtitled compound. Yield 0.155 mg.
Reaction SMILES: Cl.[CH2:2]([O:4][CH:5]([O:8][CH2:9][CH3:10])[CH2:6][NH2:7])[CH3:3].[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][C@H:17]1[CH2:21][C:20](OCC)=[N:19][CH2:18]1)([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([Si:15]([CH3:26])([CH3:25])[O:16][C@@H:17]1[CH2:18][N:19]=[C:20]([NH:7][CH2:6][CH:5]([O:8][CH2:9][CH3:10])[O:4][CH2:2][CH3:3])[CH2:21]1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(CN)OCC
Reactant: CCOC1=NC[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: Cl
Solvent: CCO
Product: CCOC(CNC1=NC[C@@H](O[Si](C)(C)C(C)(C)C)C1)OCC
Temperature: 25 °C
Reaction time: 16 h
Yield: 434.4 %

Procedure:
Ethanolic hydrogen chloride (1M, 420 mL) was added dropwise to a solution of aminoacetaldehyde diethyl acetal (55.1 g, 0.14 mol) and the compound isolated in Step 2 (101 g, 0.41 mol) in ethanol (1500 mL). This mixture was stirred at room temperature for 16 hours, and then evaporated under reduced pressure. The resulting solid was recrystalised from ether to give [(S)-4-(tert-butyl-dimethyl-silanyloxy)-4,5-dihydro-3H-pyrrol-2-yl]-(2,2-diethoxy-ethyl)-amine as a solid (201 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[N:17]=[C:16]([NH2:28])[N:15]=1>CN(C=O)C>[NH2:28][C:16]1[N:15]=[C:14]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][S:9]([NH2:12])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=2)[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[O:26][CH3:27])[N:17]=1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Reactant: COc1ccccc1-c1cc(Cl)nc(N)n1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1cc(Nc2cccc(CS(N)(=O)=O)c2)nc(N)n1
Temperature: 85 °C

Procedure:
A mixture of (3-amino-phenyl)-methanesulfonamide (0.16 g, 0.85 mmol) and 4-chloro-6-(2-methoxyphenyl)-pyrimidin-2-ylamine (0.2 g, 0.85 mmol) in DMF (5 mL) was stirred at 80-90° C. till the reaction completion (TLC control), then evaporated in vacuo. The resulting residue was purified by column chromatography on silica gel yielding {3-[2-amino-6-(2-methoxy-phenyl)-pyrimidin-4-ylamino]-phenyl}-methanesulfonamide
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH3:40]>>[CH2:39]([N:38]([CH2:37][CH2:36][O:35][CH3:34])[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6])[CH3:40]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: CCNCCOC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCN(CCOC)c1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-(2methoxyethyl)ethylamine. ES-MS m/e (%): 472 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[I:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:32](Br)[CH:33]=[CH2:34].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([C:9]1[CH:18]=[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][C:13]([C:27]#[N:28])=[CH:14][CH:15]=2)[C:10]=1[I:29])[CH2:34][CH:33]=[CH2:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)Nc1cc(OCc2ccccc2)c2ccc(C#N)cc2c1I
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN(C(=O)OC(C)(C)C)c1cc(OCc2ccccc2)c2ccc(C#N)cc2c1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
A solution of 27 (160 mg, 0.31 mmol) in anhydrous DMF (5 mL) under Ar was treated with NaH (19 mg, 0.47 mmol, 1.5 equiv, 60% oil dispersion) and the reaction mixture was stirred for 30 min at 0° C. Allyl bromide (194 mg, 139 μL, 1.55 mmol, 5 equiv) was added dropwise over 5 min and the solution was allowed to warm to 25° C. and stirred for 2 h. Saturated aqueous NaHCO3 (10 mL) was added and the aqueous phase was extracted with EtOAc (4×10 mL), dried (Na2SO4) and concentrated. Chromatography (SiO2, 2×15 cm, 10% EtOAc-hexane) afforded 28 (155 mg, 168 mg theoretical, 92%) as a clear oil which crystallized under vacuum: 1H NMR (CDCl3, 400 MHz) δ8.60 (s, 1H), 8.38 (d, 1H, J=8.6 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.47-7.34 (m, 5H), 6.90 and 6.79 (two s, 1H), 5.94-5.84 (m, 1H), 5.27 and 5.22 (two d, 2H, J=12.3 Hz), 5.00 (m, 2H), 4.50 (dd, 1H, J=5.3, 14.4 Hz), 3.81 (dd, J=7.0, 14.4 Hz), 1.57 and 1.29 (two s, 9H); 13C NMR (CDCl3, 100 MHz) δ154.8, 144.9, 138.7, 135.7, 134.8, 133.2, 128.8, 128.3, 127.3, 126.9, 126.8, 124.2, 118.8, 118.4, 117.2, 112.2, 110.7, 80.8, 70.7, 53.3, 52.0, 28.4; IR (film) vmax 2977, 2228, 1703, 1593, 1503, 1410, 1368, 1324, 1250, 1223, 1150, 1108, 931, 830, 735, 696 cm-1 ; FABHRMS (NBA-CsI) m/z 672.9948 (M+ +Cs, C26H25IN2O3, requires 672.9964).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]1([O:17][CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:14]1[CH:15]=[CH:16][C:11]([O:17][CH3:18])=[CH:12][CH:13]=1)=[O:5]
Reactant: COc1ccccc1
Reactant: O=C(Cl)c1ccccc1F
Product: COc1ccc(C(=O)c2ccccc2F)cc1

Procedure:
The process of Example 1 was followed except for the following: in Step 4, 2-fluorobenzoyl chloride was used in place of 3-methylbenzoyl chloride and reacted with anisole in place of benzene to yield 2-fluoro-4'-methoxybenzophenone; in Step 5, 2-fluoro-4'-methoxybenzophenone was used in place of 3-methylbenzophenone to produce 1-(2-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol; and in Step 6, 1-(2-fluorophenyl)-1-(4-methoxyphenyl)-2-propyn-1-ol was used in place of 1-(3-methylphenyl)-1-phenyl-2-propyn-1-ol. The recovered product, about 4.0 grams, had a melting point of 144° to 146° C. A nuclear magnetic resonance (NMR) spectrum showed the recovered product to have a structure consistent with 7-(2-fluorophenyl)-7-(4-methoxyphenyl)-7H-2-methyl-2,3-dihydrofuro[3',2',:5,6]naphtho[2,1-b]pyran.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][OH:20])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([NH:6][C:7]1[NH:8][C:9](=[O:24])[C:10]2[N:11]=[CH:12][N:13]([C:22]=2[N:23]=1)[C@@H:14]1[O:21][C@H:18]([CH2:19][O:20][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[C@@H:16]([OH:17])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
N2-isobutyryl-2′-deoxyguanosine (20.5 g) was dissolved in 200 ml of DMF. After 18.5 g of imidazole was dissolved in the resultant solution by addition, 21.4 g of tert-butyldimethylsilyl chloride was then added. DMF (100 ml) was further added and the solution was stirred at room temperature. After 8 hours, extraction using chloroform was carried out and the organic layer was washed by a saturated aqueous solution of sodium chloride and dried with anhydrous magnesium sulfate. After concentration of the extract, the target compound was separated by column chromatography (methanol/chloroform). The fraction solution including the target compound was prepared and concentrated to obtain 20.5 g of the titled compound (yield; 74%).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[N+:5]([CH2:8][CH2:9][C:10](Cl)=[O:11])([O-:7])=[O:6].C([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)CCCCCCC.Cl>C(Cl)Cl>[N+:5]([CH2:8][CH2:9][C:10]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:11])([O-:7])=[O:6]
Reactant: CCCCCCCCc1ccccc1
Reactant: O=C(Cl)CC[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CC[N+](=O)[O-])c1ccccc1
Temperature: 2.5 °C
Yield: 76 %

Procedure:
AlCl3 (12.0 g, 89.0 mmol) was added to 15 ml of methylene chloride and cooled to 0-5° C., following by addition of 3-nitropropanoyl chloride (11 g, 80 mmol). Octylbenzene (17.10 g, 89.0 mmol) in 40 ml of CH2Cl2 was dropwise added and the solution was stirred at room temperature under TLC monitoring. After reaction completion, the mixture was poured onto ice, acidified by addition of 2 M HCl to pH 2, and extracted with CH2Cl2. The combined organic extracts were washed again with 2 M HCl and water, dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to yield a solid that was recrystallized (hexanes) to give 3-nitro-1-phenylpropan-1-one (76%); mp 59-62° C., ESIMS 292 [M+H]+.