Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11][CH3:12])=[O:10])[CH:4]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:8][N:7]1[C:3]([CH2:2][O:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][C:5]([C:9]([O:11][CH3:12])=[O:10])=[N:6]1
Reactant: COC(=O)c1cc(CO)n(C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(COS(C)(=O)=O)n(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cooled solution of methyl 5-(hydroxymethyl)-1-methyl-1H-pyrazole-3-carboxylate (0.60 g, 3.51 mmol) and triethylamine (1.22 mL, 8.77 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.41 mL, 5.26 mmol). The reaction mixture was stirred in the ice bath for 15 minutes and then the mixture was allowed to warm to room temperature. The reaction mixture was stirred at RT for 1 hour. The reaction mixture was diluted with DCM and washed with water and brine. The organic phase was dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo. The crude material was used in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([N:14]3[CH2:18][CH2:17][C@@H:16]([NH:19]C(=O)OC(C)(C)C)[CH2:15]3)=[O:13])[CH:8]=2)[CH2:3]1.Cl>C1COCC1>[NH2:19][C@@H:16]1[CH2:17][CH2:18][N:14]([C:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]3)=[O:13])[CH2:15]1
Reactant: CN1CCc2cc(C(=O)N3CC[C@@H](NC(=O)OC(C)(C)C)C3)ccc2C1
Agent: Cl
Solvent: C1CCOC1
Product: CN1CCc2cc(C(=O)N3CC[C@@H](N)C3)ccc2C1
Reaction time: 2 h

Procedure:
1.4 g (3.8 mmol) tert. Butyl (R)-[1-(2-methyl-1,2,3,4-tetrahydroisoquinoline-6-carbonyl)-pyrrolidin-3-yl]-carbamate are dissolved in 5 ml THF and slowly combined with 9.5 ml hydrochloric acid (4 M in 1,4-dioxane). The mixture is stirred for two hours, then concentrated down to ⅔ of its volume and the crude product is filtered off as a precipitate, which is then purified by RP-HPLC (eluant: gradient ammonia/acetonitrile).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]1=O)(=O)[CH3:2].[CH3:12][CH:13]([C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([CH:27]=1)[OH:26])[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl>C(O)(=O)C>[CH3:12][CH:13]([C:21]1[CH:27]=[C:25]([OH:26])[C:24]2[CH:1]([CH3:2])[C:4]3[CH2:9][CH2:8][CH:7]([CH3:10])[CH2:6][C:5]=3[O:28][C:23]=2[CH:22]=1)[CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CC(=O)C1CCC(C)CC1=O
Reactant: CCCCCC(C)C(C)c1cc(O)cc(O)c1
Agent: Cl
Solvent: CC(=O)O
Product: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C
Reaction time: 20 h

Procedure:
A solution of 3.6 g. of 2-acetyl-5 -methylcyclohexanone and 5.6 g. of 5-(1,2-dimethylheptyl)resorcinol in 150 ml. of acetic acid is cooled to 15° and saturated with hydrogen chloride gas. The solution is allowed to warm to 25°, stirred for 20 hours and then heated for one hour on a steam bath. The reaction mixture is concentrated in vacuo, water is added and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with water, dried (MgSO4) and concentrated to give a residue which is distilled five times, b.p. 195°-200° (0.025 mm.). The distillate is chromatographed on silica gel with benzene as eluant. The second fraction is collected and distilled to give the title compound, b.p. 190°-195° (0.05 mm.).
Reaction SMILES: [F-:1].[F:2][C:3]([F:14])([C:11](Cl)=[O:12])[O:4][C:5]([F:10])([F:9])[C:6](Cl)=[O:7].[F-:15].[Na+]>C(#N)C>[F:2][C:3]([F:14])([C:11]([F:15])=[O:12])[O:4][C:5]([F:10])([F:9])[C:6]([F:1])=[O:7]
Reactant: O=C(Cl)C(F)(F)OC(F)(F)C(=O)Cl
Reactant: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(F)C(F)(F)OC(F)(F)C(=O)F
Reaction time: 8 h

Procedure:
Conversion of the diacid chloride to the corresponding fluoride, bp 32°-33° C., was accomplishd by a scale-up of the procedure of R. E. Banks, E. D. Burling, B. A. Dodd, and K. Mullen, J. Chem. Soc. (c), 1706 (1969). A mixture of 215 g 0.885 mol) of tetrafluorodiglycolyl dichloride, 140.5 g (3.35 mol) of NaF, and 1200 ml of anhydrous acetonitrile was stirred overnight, then distilled to give a fraction collected at 35°-79° C. The distillate was treated with 20 g of NaF and distilled to give 105 g of tetrafluorodiglycolyl difluoride, bp 32°-33° C. Addition of another 100 g (2.38 mol) of NaF to the reaction mixture and slow distillation afforded another fraction, bp 35°-81° C. Treatment with 10 g of NaF and fractionation gave another 37.0 g of difluoride product, bp 32°-33° C., for a total of 142 g (76%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9](I)[S:8][C:6]=2[N:7]=1.[CH3:18][S:19]([NH:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:20]>>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[N:10]=[C:9]([C:27]3[CH:28]=[C:23]([NH:22][S:19]([CH3:18])(=[O:20])=[O:21])[CH:24]=[CH:25][CH:26]=3)[S:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Nc1cccc(B(O)O)c1
Reactant: Clc1nc(N2CCOCC2)c2nc(I)sc2n1
Product: CS(=O)(=O)Nc1cccc(-c2nc3c(N4CCOCC4)nc(Cl)nc3s2)c1

Procedure:
4-(5-Chloro-2-iodothiazolo[5,4-d]pyrimidin-7-yl)morpholine 18 was reacted with 3-(methylsulfonylamino)phenylboronic acid via General Procedure A to give crude 3-(5-chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)-N-methylsulfonylbenzenamine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A again to give 121 after purification by reverse HPLC. MS (Q1) 485 (M+)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH:18]C(=O)C3C=CC=CC=3)=[N:9]2)[CH:7]=1.N12CCCN=C1CCCCC2>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]2([CH2:27][F:28])[CH2:13][C@@H:12]([C:14]([F:17])([F:15])[F:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1
Reactant: Nc1ccc(F)c([C@]2(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c3ccccc3)=N2)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: NC1=N[C@](CF)(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)O1
Temperature: 80 °C
Yield: 82.2 %

Procedure:
A microwave vial was charged with a solution of crude N-((4S,6S)-4-(5-amino-2-fluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1k, 0.561 g, 1.357 mmol, Example 1 step 9) in MeOH (9 mL). 1,8-diazabicyclo[5.4.0]undec-7-ene (1.653 g, 10.86 mmol, Aldrich) was added and the vial was sealed. The reaction was heated to 80° C. in a microwave (Biotage Initiator) for a total of 135 minutes. The reaction was concentrated under reduced pressure. The crude material was taken up in EtOAc and washed with water (3×). The organic layer was extracted with 1N HCl (two times). The acidic aqueous layer was washed with EtOAc (twice). The acidic aqueous layer was basified with 5N NaOH to pH=12 and back extracted with EtOAc (twice). The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to afford the crude title compound as a grey oil (0.345 g, 1.116 mmol, 82% crude yield) which was used in the next step without further purification. MS m/z=310.0 [M+H]+. Calculated for C12H12F5N3O: 309.235
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[N:30]1([C:36]([NH2:38])=[O:37])[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6]([C:5]3[CH:28]=[CH:29][C:2]([N:33]4[CH2:34][CH2:35][N:30]([C:36]([NH2:38])=[O:37])[CH2:31][CH2:32]4)=[N:3][CH:4]=3)=[O:7])=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: NC(=O)N1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: NC(=O)N1CCN(c2ccc(C(=O)NCc3cn(-c4ccccc4)c4cc(Cl)ccc4c3=O)cn2)CC1

Procedure:
4-{5-[(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamoyl]-pyridin-2-yl}-piperazine-1-carboxylic acid amide was prepared starting from intermediate E and piperazine-1-carboxylic acid amide. MS calcd. for C27H25ClN6O3 [(M+H)+] 517.2, obsd. 517.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C@@H:23]12[C:32](=[O:33])[O:31][C:29](=[O:30])[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2>C(OCC)C>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:32]([C@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@H:24]3[C:29]([OH:31])=[O:30])=[O:33])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)[C@H]3CCCC[C@H]3C(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h
Yield: 70.3 %

Procedure:
To a solution of 2.97 g of 4'-amino-3,5-di-t-butyl-4-hydroxybiphenyl in 200 ml of diethyl ether was added a solution of 1.54 g (0.01 mole) of cis-1,2-cyclohexanedicarboxylic anhydride in 75 ml of diethyl ether, and the resulting solution was stirred for about 16 hours. A solid was removed by filtration, rinsed with diethyl ether and hexane and then recrystallized from a mixture of ethyl acetate and hexane to give 3.17 g of solid cis-2-{N-[4-(3,5-di-t-butyl-4-hydroxyphenyl)phenyl]carbamyl}-cyclohexanecarboxylic acid, m.p. 217°-220° C. Analysis: Calculated for C28H37NO4 : % C, 74.5; % H, 8.3; % N, 3.1; Found: % C, 74.6; % H, 8.3; % N, 3.0.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=O.O.[CH3:27][N:28](C)C=O>CN.C(O)C>[CH3:27][NH:28][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:2]
Reactant: CN(C)C=O
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: CN
Solvent: O
Solvent: CCO
Product: CNC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Reaction time: 48 h

Procedure:
300 mg (0.87 mmol) (RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester is dissolved in a mixture of 1 ml N,N-dimethylformamide and 0.18 ml of a 33% solution of methylamine in ethanol. The reaction vessel is tightly stopped and hold at 120° C. for 48 hours. Water is added and the product extracted with ethyl acetate. Drying and evaporation yields 92 mg (31%) of a slightly yellowish product. MS: m/e=343.3 (M+H)+.
Reaction SMILES: [C:1]([NH:9][C:10](=[N:13][CH3:14])SC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[C:1]([NH:9][C:10]([NH:13][CH3:14])=[N:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN=C(NC(=O)c1ccccc1)SC
Reactant: NCCCCCCCCN
Product: CNC(=NCCCCCCCCN)NC(=O)c1ccccc1

Procedure:
A mixture of N-benzoyl-N'-methyl-S-methylisothiourea and an excess of 1,8-diaminooctane is maintained at 60° for 5 hours to give a solid product which is washed with ether to leave N-benzoyl-N'-methyl-N"-(8-aminooctyl)guanidine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:7]2[N:8]=[C:9]([N:12]3[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]3)[CH:10]=[CH:11][C:6]2=[N:5][N:4]=1.Br[C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>>[OH:18][C:15]1([C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[CH2:16][CH2:17][N:12]([C:9]2[CH:10]=[CH:11][C:6]3[N:7]([C:3]([C:2]([F:1])([F:19])[F:20])=[N:4][N:5]=3)[N:8]=2)[CH2:13][CH2:14]1
Reactant: O=C1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Reactant: N#Cc1cccc(Br)c1
Product: N#Cc1cccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)c1
Yield: 26 %

Procedure:
A mixture of 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-one and 3-bromobenzonitrile was allowed to react by the method of Example 315 to give 3-[4-hydroxy-1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]benzonitrile in 26% yield.
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:20][O-:21].[Na+]>>[OH:19][CH:16]([CH2:17][OH:18])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([O:21][CH3:20])[C:11]=2[N:12]=[CH:13]1
Reactant: OCC(O)Cn1cnc2c(Cl)nc3ccccc3c21
Reactant: C[O-]
Agent: [Na+]
Product: COc1nc2ccccc2c2c1ncn2CC(O)CO

Procedure:
Using the method of Example 157, 4-chloro-1-(2,3-dihydroxypropyl)-1H-imidazo[4,5-c]quinoline (from Example 124, Part D) was reacted with sodium methoxide to provide 1-(2,3-dihydroxypropyl)-4-methoxy-1H-imidazo[4,5-c]quinoline, m.p. 214°-216° C. after recrystallization from isopropanol. Analysis: Calculated for C14H15N3O3 : %C, 61.5; %H, 5.5; N, 15.4; Found: %C, 61.3; %H, 5.5; %N, 15.4.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH2:17][CH:18]3[CH2:22][CH2:21][CH2:20][O:19]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>CO>[NH2:25][C:9]1[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH2:17][CH:18]1[CH2:22][CH2:21][CH2:20][O:19]1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCC1CCCO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1nc(OCCC2CC2)nc2c1[nH]c(=O)n2CCC1CCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a solution of 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-9-[2-(tetrahydro-2-furanyl)ethyl]-9H-purin-6-amine (88 mg, 0.253 mmol) in methanol (10 ml) at room temperature was added 4M HCl in 1,4 dioxane (2.106 ml, 8.42 mmol) to give a pale straw coloured solution. The reaction mixture was stirred at ambient temperature overnight (16 hours) and then loaded in methanol onto a 5 g aminopropyl SPE cartridge and eluted with methanol. The filtrate was evaporated on a nitrogen blowdown unit to give the title compound as a white solid (41 mg).
Reaction SMILES: [Li+].[BH4-].[F:3][C:4]1([F:26])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]([F:21])([F:20])[F:19])[CH:10]=2)[C@H:6]([C:22](OC)=[O:23])[CH2:5]1>C1COCC1.C(OCC)(=O)C>[F:26][C:4]1([F:3])[CH2:8][N:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([C:18]([F:20])([F:21])[F:19])[CH:10]=2)[C@H:6]([CH2:22][OH:23])[CH2:5]1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CC(F)(F)C[C@H]2CO)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of LiBH4 (55 mg, 2.54 mmol) in anhydrous THF (3 mL) was added a solution of (S)-methyl 4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine-2-carboxylate (300 mg, 0.85 mmol) in anhydrous THF at 0° C. The reaction mixture was stirred at 0° C. for 20 min then allowed to come to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water (50 mL), and then brine. The layers were separated, and the organic layer was dried over Na2SO4, filtered, and concentrated to afford (S)-(4,4-difluoro-1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidin-2-yl)methanol as a yellow, viscous oil (275 mg, 100%). LC/MS: m/z 327.2 (M+H)+ at 1.54 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]O.C(N(CC)C(C)C)(C)C.S(Cl)([Cl:26])=O>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][Cl:26]
Reactant: O=S(Cl)Cl
Reactant: COCOc1c(CO)cccc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COCOc1c(CCl)cccc1OC
Reaction time: 0.25 h

Procedure:
2.34 g (11.8 mmol) of 2-methoxymethoxy-3-methoxybenzyl alcohol was dissolved in 20 ml of diethyl ether, and the resultant solution was added with 1.53 g (11.8, mmol) of N,N-diisopropylethylamine. To the obtained solution was fed dropwise 1.40 g (11.8 mmol) of thionyl chloride and diethyl ether (15 ml) in a manner of spending 15 min. while cooling the solution with ice. The temperature of the resultant mixture was then brought back to a room temperature, and the mixture was stirred all night. The insoluble materials therein are removed by filtration, and the filtrate was condensed under reduced pressure to thereby obtain a crude product of 2-methoxymethoxy-3-methoxybenzyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].[CH2:12]=[S:13]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]=[C:12]=[S:13]
Reactant: C=S
Reactant: Nc1cc([N+](=O)[O-])ccc1Cl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)c(N=C=S)c1

Procedure:
A mixture of 50 parts of 2-chloro-5-nitrobenzenamine, 33.4 parts of methanethial and 450 parts of 1,4-dioxane is stirred and refluxed for 4 hours. The reaction mixture is evaporated, yielding 62.2 parts of 1-chloro-2-isothiocyanato-4-nitrobenzene as a residue.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([N:13](C1C=CC=CC=1)[C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH3:15])=[O:12].C=O.[C:34](O)(=O)[CH3:35]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]([NH:13][C@H:14]([C:16]([NH:18][C@H:19]([CH:24]=[O:25])[CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH2:15][C:35]1[CH:34]=[CH:5][CH:4]=[CH:3][CH:11]=1)=[O:12]
Reactant: CC(=O)O
Reactant: C[C@@H](C(=O)N[C@H](C=O)CC(=O)O)N(C(=O)c1cc2ccccc2n1C)c1ccccc1
Agent: C=O
Solvent: CO
Product: Cn1c(C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@H](C=O)CC(=O)O)cc2ccccc21
Yield: 25 %

Procedure:
(3S)-3-[(1-Methylindole-2-carbonyl)phenyl-alaninyl]amino-4-oxobutanoic acid, semicarbazone (116 mg, 0.25 mmol) were dissolved in methanol (3 mL), formaldehyde (1 mL, 37% wt. aq) and acetic acid (1 mL) and the resulting solution was stirred for 9 hours under a nitrogen atmosphere at room temperature. The reaction mixture was concentrated in vacuo diluted with water, and extracted twice with ethyl acetate. The ethyl acetate solution was washed with brine, dried over sodium sulfate and concentrated to give a crude product which was triturated with ether to afford the title product as a brown powder (26 mg, 25%). TLC: (methylene chloride:methanol:acetic acid, 20:1:1, silica gel): Rf=0.33; MS(EI) for C23H21N3O5; M+H+=422; M−H+=420.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([C:9]1[N:17]2[C:12]([CH2:13][O:14][CH2:15][CH2:16]2)=[C:11]([C:18]([OH:20])=O)[CH:10]=1)=[O:8].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:43]1([C@H:49]([NH2:52])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>CN(C)C=O.O>[C:43]1([C@H:49]([NH:52][C:18]([C:11]2[CH:10]=[C:9]([C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C@@H:2]3[CH3:1])=[O:8])[N:17]3[CH2:16][CH2:15][O:14][CH2:13][C:12]=23)=[O:20])[CH2:50][CH3:51])[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: C[C@H]1CCCN1C(=O)c1cc(C(=O)O)c2n1CCOC2
Reactant: CC[C@@H](N)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccccc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid (Comp. No. 7c) (300 mg, 0.914 mmol) in dimethylformamide (4 ml) was added 1-hydroxybenzotriazole (136 mg, 1 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (193 mg, 1 mmol). The mixture was stirred for 90 min at 50° C., then (R)-1-phenyl-propylamine (85 mg, 1 mmol) was added and the mixture was stirred at 25° C. overnight. An excess of water was added, the solid which precipitated was filtered off, washed with a small amount of water and purified by reverse phase HPLC (acetonitrile/water gradient with 0.1% trifluoroacetic acid) to give 243 mg (67%) of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid ((R)-1-phenyl-propyl)-amide (Comp. No. 16a; compounds with a compound number starting with “16” are compounds of the formula I) as white solid. LC/MS (method 4): Rt=1.12 min; m/z=396.22 (M+H+). 1H-NMR: δ (ppm)=8.07 (1H, d), 7.26-7.35 (5H, m), 7.19-7.22 (1H, m), 4.98 (1H, d), 4.81-4.89 (2H, m), 4.17-4.30 (2H, m), 3.92-3.99 (2H, m), 3.80-3.85 (1H, m), 3.68 (2H, bs), 2.03-2.09 (1H, m), 1.92-1.99 (1H, m), 1.74-1.84 (3H, m), 1.53-1.59 (1H, m), 1.18 (3H, d), 0.88 (3H, t).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[N:28](COCC3C=CC=CC=3)[C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][OH:46])[C@@H:21]1[OH:47])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd]>[Si:1]([O:18][CH2:19][C@H:20]1[O:24][C@@H:23]([N:25]2[CH:32]=[C:31]([CH3:33])[C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:43][CH2:44][CH2:45][OH:46])[C@@H:21]1[OH:47])([C:14]([CH3:16])([CH3:15])[CH3:17])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCO)c(=O)n(COCc2ccccc2)c1=O
Agent: [Pd]
Product: Cc1cn([C@@H]2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@H]2OCCO)c(=O)[nH]c1=O

Procedure:
5′-O-t-Butyldiphenylsilyl-3-benzyloxymethyl-2′-O-(hydroxyethyl)-5-methyluridine prepared in Example 31 above is hydrogenated using 10% Pd on carbon as per the procedure of Example 35 above to give the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](Cl)=[O:12].[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(OCC)(=O)C>[C:14]([NH:18][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ccc2ccccc2c1

Procedure:
Following the procedure of Example 1 above and using 2-naphthoyl chloride and tert-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a white solid, m.p. 154.8-159.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:5][CH2:6][C:7]1[NH:8][CH:9]=[C:10]([CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)[C:11](=[O:13])[N:12]=1.[Cu][C:26]#[N:27]>CN1C(=O)CCC1>[F:24][C:23]1[CH:22]=[CH:21][C:4]([CH2:5][CH2:6][C:7]2[NH:8][CH:9]=[C:10]([CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[N:19][CH:20]=3)[C:11](=[O:13])[N:12]=2)=[CH:3][C:2]=1[C:26]#[N:27]
Reactant: N#C[Cu]
Reactant: O=c1nc(CCc2ccc(F)c(Br)c2)[nH]cc1Cc1cncnc1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CCc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1F
Temperature: 200 °C
Yield: 80.6 %

Procedure:
A mixture of 2-(3-bromo-4-fluorophenethyl)-5-(pyrimidin-5-ylmethyl)pyrimidin-4(1H)-one (1.5 g, 3.7 mmol), copper(I) cyanide (399 mg, 4.4 mmol) in NMP (5 mL) was heated with a microwave reactor at 200° C. for 1.5 h. After cooling to room temperature, the mixture was filtered. The filtrate was partitioned between ethyl acetate (20 mL) and water (30 mL). The organic phase was collected, washed with water (30 mL×2), brine (20 mL), dried over Na2SO4, filtered, and concentrated to give the title compound as a gray solid (1.0 g, 55% yield), which was used without further purification. LCMS: rt=1.31 min, [M+H+]=336