Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[S:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[C:10]=1[OH:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH3:23][NH2+:24][CH3:25]>>[CH3:23][N:24](/[C:1](/[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[C:9]1\[C:10](=[O:18])[C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[S:13]\1)[CH3:25]
Reactant: C[NH2+]C
Reactant: O=C(c1ccccc1)c1sc2ccccc2c1O
Agent: CC(=O)[O-]
Product: CN(C)/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Yield: 18 %

Procedure:
Prepared as in Example 31 from 2-benzoyl-benzo[b]thiophen-3-ol and dimethylammonium acetate with a yield of 18% of theory; m.p. 179°-180° C. (ethyl acetate/petroleum ether 1:2). The product was identical to that prepared according to Example 4, based on its thin-layer chromatogram, elemental analysis and IR-spectrum.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1.[CH:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[O:20][C:19]2=O>>[N:17]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[N:9]1[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]2[C:19](=[O:20])[CH:18]3[CH2:25][CH:22]([CH2:23][CH2:24]3)[C:21]2=[O:26])[CH2:11][CH2:10]1
Reactant: O=C1OC(=O)C2CCC1C2
Reactant: NCCCCN1CCN(c2ncccn2)CC1
Product: O=C1C2CCC(C2)C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 34 %

Procedure:
The title compound was prepared from 1.92 g (8.2 mmol) of 1-(4-aminobutyl)-4-(2-pyrimidinyl)piperazine and 1.14 g (8.14 mmol) of 3-oxabicyclo[3.2.1]octan-2,4-dione, substantially following the procedure of Example 1. Yield: 1.0 g (34% yield).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[N+:18]=[N-:19]
Reactant: BrCc1c2ccccc2cc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 9-bromomethyl-anthracene (7.85 g, 29.0 mmol) and sodium azide (7.79 g, 120 mmol) in dimethylformamide (DMF, 190 mL) was heated at 50° C. for 30 minutes. The mixture was cooled to room temperature, and extracted with ether, and the ether layers were washed with water, dried over MgSO4 and concentrated to give 9-azidomethyl-anthracene as yellow crystals (5.92 g, 87% yield). 1H NMR (CDCl3) δ 8.53 (1H, s), 8.31 (2H, d), 8.07 (2H, d), 7.61 (2H, dd), 7.53 (2H, dd), 5.35 (2H, s).
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:4]([N:17]=[C:18]=[S:19])=[CH:5][C:6]([O:15][CH3:16])=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[CH:8]=1>>[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[NH:17][C:18]([NH2:1])=[S:19]
Reactant: N
Reactant: COc1cc(N=C=S)c(F)cc1-n1cnc(C)n1
Product: COc1cc(NC(N)=S)c(F)cc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100.5 %

Procedure:
Step B (4): Methanolic ammonia (1.0 M, 25 mL, 25 mmol) was added to a flask charged with 1-(5-fluoro-4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (870 mg, 3.29 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated in vacuo. The resulting solid was dried under high vacuum to afford 1-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (930 mg, 100% yield). LC-MS (M+H)+ 282.1. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.84 (s, 1 H) 7.88 (d, J=6.41 Hz, 1 H) 7.57 (d, J=10.99 Hz, 1 H) 3.86 (s, 3 H) 2.36 (s, 3 H).
Reaction SMILES: [F:1][CH:2]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[CH:22][N:21]=3)[CH:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:38][CH:39]=O>>[CH2:38]([N:35]1[CH2:34][CH2:33][N:32]([CH:2]([F:1])[C:3]2[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=5)[CH:23]=[CH:22][N:21]=4)[CH:13]=3)=[O:10])=[CH:5][CH:4]=2)[CH2:37][CH2:36]1)[CH3:39]
Reactant: Cc1ccc(NC(=O)c2ccc(C(F)N3CCNCC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC=O
Product: CCN1CCN(C(F)c2ccc(C(=O)Nc3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc2)CC1

Procedure:
The product from Example 3 was ethylated via reductive amination with CH3CHO/NaBHCN afforded the title compound. Mass: (M+1), 526.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]([F:31])([F:32])[C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])=[O:7])=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound (D144) (60 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and and 4-(trifluoromethyl)-benzylbromide (0.056 ml). (Na2CO3; reaction time: 5 hrs; 70° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:48].ClCCl.CO.ClCl>ClCCl>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])(=[O:48])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](CCS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 46 %

Procedure:
Prepared analogously to Example 85 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfinylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and 2 equivalents of 3-chloroperoxybenzoic acid in dichloromethane/glacial acetic acid. Yield: 46%; Rf value: 0.38 (silica gel; dichloromethane/methanol=9:1); C29H35Cl2N5O6S (652.60); mass spectrum: (M+H)+=652/654/656 (chlorine isotope).
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:13][C:10]([C:14](=O)[NH:15][C:16]3[C:17](=[O:30])[N:18]([CH2:27][CH2:28][CH3:29])[C:19](=[O:26])[N:20]([CH2:23][CH2:24][CH3:25])[C:21]=3[NH2:22])([CH2:11][CH2:12]1)[CH2:9][CH2:8][CH2:7]2)=[O:5])C>[OH-].[Na+].CO>[O:26]=[C:19]1[N:20]([CH2:23][CH2:24][CH3:25])[C:21]2[N:22]=[C:14]([C:10]34[CH2:13][C:6]([C:4]([OH:3])=[O:5])([CH2:12][CH2:11]3)[CH2:7][CH2:8][CH2:9]4)[NH:15][C:16]=2[C:17](=[O:30])[N:18]1[CH2:27][CH2:28][CH3:29]
Reactant: CCCn1c(N)c(NC(=O)C23CCCC(C(=O)OCC)(CC2)C3)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCn1c(=O)c2[nH]c(C34CCCC(C(=O)O)(CC3)C4)nc2n(CCC)c1=O
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 5-(6-amino-2,4-dioxo-1,3-dipropyl-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl)-bicyclo[3.2.1]octane-1-carboxylic acid ethyl ester (0.238 mmol, 0.10 g) in 20% NaOH (2.0 ml) and MeOH (10.0 ml) was stirred and refluxed 5 h. The reaction was cooled to room temperature and then concentrated to remove MeOH. The aqueous was acidified (pH 2-3) with conc. HCl and then extracted with EtOAc. The combined EtOAc extracts were washed with H2O and brine, and dried (MgSO4). Filtration and evaporation followed by reverse phase HPLC provided product (0.039 g, 42%) as a solid.
Reaction SMILES: CCN(C(C)C)C(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.[NH:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27].[C:28]([O:32][C:33]([NH:35][C@H:36]([CH2:40][O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C:37](O)=[O:38])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[Si:42]([O:41][CH2:40][C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:30])[CH3:29])[C:37]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:38])([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)O
Reactant: N#C[C@@H]1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(=O)N1CCC[C@H]1C#N

Procedure:
A mixture of DIPEA (0.542 ml, 3.11 mmol) and (S)-pyrrolidine-2-carbonitrile 4-methylbenzenesulfonate (0.269 g, 1.002 mmol) in DCM was added to a mixture of (R)-2-(tert-butoxycarbonylamino)-3-(tert-butyldimethylsilyloxy)propanoic acid (0.320 g, 1.002 mmol) and HATU (0.381 g, 1.002 mmol) in DMF. After 3 h the mixture was washed with 1N citric acid and saturated sodium bicarbonate and brine. The organic layer was dried sodium sulfate, filtered and purified by column chromatography using hexane-ethylacetate as eluents.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]=[C:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([CH3:14])[CH3:13])[CH2:7][CH2:6]1>C(OC(=O)C)C.[Pd]>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([O:11][CH:12]([CH3:13])[CH3:14])[CH2:7][CH2:6]1
Reactant: COC(=O)C=C1CCC(OC(C)C)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CC1CCC(OC(C)C)CC1

Procedure:
Prepared from (4-isopropoxy-cyclohexylidene)-acetic acid methyl ester (0.500 g, 2.36 mmol) by hydrogenation 16 hours at room temperature using Pd/C (10%) (50 mg) in ethylacetate (15 ml). cis/trans mixture. MS (m/e): 215.4 (M+H+).
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8](OC)=[O:9])=[CH:6][C:5]=1[C:14]([F:17])([F:16])[F:15].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(Cl)Cl>[F:1][CH2:2][O:3][C:4]1[CH:13]=[CH:12][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[C:14]([F:15])([F:16])[F:17]
Reactant: COC(=O)c1ccc(OCF)c(C(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Product: OCc1ccc(OCF)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
To a cooled (−78° C.) solution of methyl 4-(fluoromethoxy)-3-(trifluoromethyl)benzoate (2.44 g, 9.68 mmol) in DCM under nitrogen was added 2.0 M LAH (4.84 mL, 9.68 mmol) by syringed. The reaction was stirred for 15 min. The reaction was quenched with water (0.484 mL) and 10% NaOH (0.968 mL). The mixture was filtered and concentrated to give the title compound as an oil (1.84 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.52 (d, J=5.68 Hz, 2H), 5.32 (t, J=5.75 Hz, 1H), 5.85-6.08 (d, J=53.44 Hz, 2H), 7.39 (d, J=8.46 Hz, 1H), 7.56-7.69 (m, 2H); 1H NMR (376 MHz, DMSO-d6) δ ppm −151.41 (s, 1F), −60.26 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)[N:7]=[C:6]2O.[Cl:28]CCl.C(Cl)(C(Cl)=O)=O>CN(C=O)C>[Cl:28][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[C:8]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[N:7]=1
Reactant: ClCCl
Reactant: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(O)c2cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cc(OC)c(OC)c(OC)c3)nc(Cl)c2cc1OC
Temperature: 5 °C

Procedure:
Into a 1-L 3-necked round-bottom flask, was placed 6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (12 g, 32.23 mmol, 1.00 equiv), dichloromethane (400 mL) and DMF (cat.) (0.1 g). This was followed by the addition of (COCl)2 (40 g, 315.21 mmol, 9.78 equiv) dropwise with stirring at 0-10° C. The resulting solution was heated to reflux for 5 h. The mixture was cooled to room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 400 mL of dichloromethane. The resulting mixture was washed with 2×200 mL of NaHCO3 (sat.) and 1×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/ethyl acetate (2:1). This resulted in 5 g (40%) of 4-chloro-6,7-dimethoxy-2-(3,4,5-trimethoxyphenyl)quinazoline as a yellow solid. MS (ESI) m/z 391 [M+H]+
Reaction SMILES: [OH:1][C:2]1([CH2:16][C:17](O)=O)[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:20][NH:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH3:34])[O:31][C:28]2=[N:29][CH:30]=1>>[CH3:20][N:21]([CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[C:27]2[CH:33]=[C:32]([CH3:34])[O:31][C:28]2=[N:29][CH:30]=1)[CH2:17][CH2:16][C:2]1([OH:1])[CH2:7][CH:6]2[CH2:8][CH2:9][CH:3]1[CH:4]=[C:5]2[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(O)CC1(O)CC2CCC1C=C2c1ccccc1
Reactant: CNCCCc1cnc2oc(C)cc2c1
Product: Cc1cc2cc(CCCN(C)CCC3(O)CC4CCC3C=C4c3ccccc3)cnc2o1

Procedure:
Prepared according to procedures P2.2 to P2.3 in Example 21 using rac-(1R*,2R*,4R*)-(2-hydroxy-5-phenyl-bicyclo[2.2.2]oct-5-en-2-yl)acetic acid and methyl-[3-(2-methyl-furo[2,3-b]pyridin-5-yl)-propyl]-amine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10](=[O:30])[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=1[C:19](=O)[NH:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II>C(Cl)Cl>[C:1]([O:5][C:6](=[O:31])[NH:7][CH:8]([C:10]1[O:30][CH:19]([NH:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[C:13]2[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1C(=O)Nc1cc(F)cc(F)c1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(NC(=O)OC(C)(C)C)C1=Nc2cccc(Cl)c2C(Nc2cc(F)cc(F)c2)O1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A 100-mL, three-neck, round bottomed flask equipped with a magnetic stirrer and thermometer was purged with nitrogen and charged with compound 168 (3.30 mmol), anhydrous methylene chloride (25 mL), N,N-diisopropylethylamine (4.60 g, 35.7 mmol) and triphenylphosphine (3.98 g, 15.2 mmol). The reaction mixture was then cooled to 0-5° C. in an ice/water bath. Iodine (3.61 g, 14.2 mmol) was then added portion-wise to the reaction mixture over 1 h. Once the addition was complete, the cooling bath was removed, and the mixture was stirred at room temperature for an additional 30 min. The reaction was then quenched with 10% aqueous potassium carbonate (25 mL), the organic layer separated, dried over sodium sulfate, filtered concentrated under reduced pressure. Column chromatography of the resulting-solid (silica gel, EtOAc/hexanes) gave a 52% yield of compound 169 as a white solid. m.p. 117-118° C.; 1H NMR (DMSO-d6) δ (ppm) 7.72-7.60 (m, 2H), 7.42 (dd, 1H, J=7.6 Hz, 1.3 Hz), 7.31 (d, 1H, J=7.0 Hz), 6.95 (t, 1H, J=9.3 Hz), 6.82 (m, 2H), 4.27 (m, 1H), 1.33 (s, 9H), 1.28 (d, 3H, J=7.2 Hz); m/z=436 (M+H). The reaction described above and compound 169 are shown below.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][N:31]=1>>[CH3:25][O:26][CH2:27][CH2:28][N:29]([CH3:37])[C:30]1[N:31]=[CH:32][C:33]([NH:36][C:9]([C:11]2[O:15][C:14]([CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:34][CH:35]=1
Reactant: COCCN(C)c1ccc(N)cn1
Reactant: CCCc1nc(C2CCCCC2)oc1C(=O)ON1C(=O)CCC1=O
Product: CCCc1nc(C2CCCCC2)oc1C(=O)Nc1ccc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid {6-[(2-methoxy-ethyl)-methyl-amino]-pyridin-3-yl}-amide was prepared from 2-cyclohexyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-(2-methoxy-ethyl)-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C22H32N4O3 (m/e) 400, obsd 401 (M+H).
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1>C(O)C>[OH:17][CH2:18][CH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]1[C:2](=[S:3])[NH:1][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH2:14][CH2:15][CH3:16])[N:8]=[CH:9]2
Reactant: OCCC1Cc2ccccc2CN1
Reactant: CCCc1cc2c(N=C=S)cccc2cn1
Solvent: CCO
Product: CCCc1cc2c(NC(=S)N3Cc4ccccc4CC3CCO)cccc2cn1
Temperature: 20 °C
Reaction time: 20 h
Yield: 71.3 %

Procedure:
5-Isothiocyanato-3-propylisoquinoline (4.5 g) is added to a solution of (RS)-3-(2-hydroxyethyl)-1,2,3,4-tetrahydroisoquinoline (3.5 g) in absolute ethanol (35 cc). After stirring for 20 hours at a temperature of about 20° C., the crystals which have appeared are filtered off and then washed with ethanol (2×2 cc). (RS)-3-(2-Hydroxyethyl)-N-(3-propylisoquinol-5-yl)-1,2,3,4-tetrahydroisoquinoline-2-carbothioamide (5.7 g) is thus obtained; after recrystallisation from propanol (50 cc), it melts at 175° C.
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:33])(=[O:32])[NH:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C1COCC1>[C:30]([CH2:29][CH2:28][CH2:27][NH:26][S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:23][CH2:22]2)(=[O:33])=[O:32])#[N:31]
Reactant: CC(C)(C)OC(=O)n1ccc2c(N3CCN(S(=O)(=O)NCCCC#N)C4(CC4)C3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N#CCCCNS(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[4-(3-Cyano-propylsulfamoyl)-4,7-diaza-spiro[2.5]oct-7-yl]-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 18) was dissolved in THF (1 mL), added TFA (0.5 mL) and then stirred at rt for 2 h.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:17]([CH3:16])(=[O:19])=[O:18])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
A solution of alcohol 103 (6.33 g, 30.0 mmol) in CH2Cl2 (60 mL) was treated with TEA (6.07 g, 8.36 mL, 60 mmol, 2.0 equiv) at 25° C., and the resulting mixture was cooled to 0-5° C. before MsCl (3.78 g, 2.55 mL, 33.0 mmol, 1.1 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h under N2. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was quenched with H2O (40 mL) and CH2Cl2 (40 mL). The two layers were separated, and the aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with H2O (2×40 mL) and saturated aqueous NaCl (40 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the desired (5R)-methanesulfonic acid 3-(3-fluoro-phenyl)-2-oxo-oxazolidin-5-ylmethyl ester 109 (7.69 g, 88.7% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. C11H12FNO5S, LCMS (EI) m/e 290 (M++H).
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[C:18]([O:20]CC)=[O:19].C1COCC1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C(O)C>[C:14]([O:13][C:11]([N:4]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:10]2[CH:2]([CH3:1])[CH:3]1[C:18]([OH:20])=[O:19])=[O:12])([CH3:15])([CH3:16])[CH3:17]
Reactant: CCOC(=O)C1C(C)c2cccnc2N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1c2cccnc2N(C(=O)OC(C)(C)C)C1C(=O)O
Temperature: 25 °C
Reaction time: 168 h
Yield: 48.3 %

Procedure:
In a 100 mL round-bottomed flask, 1-tert-butyl 2-ethyl 3-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1,2-dicarboxylate (235 mg, 767 μmol, Eq: 1.00) was combined with THF (7.0 mL) and ethanol (2.3 mL) to give a colorless suspension. 1 M aqueous LiOH (2.3 mL, 2.3 mmol, Eq: 3) was added and the reaction was stirred at rt for 7 d. 0.1 M Aqueous KHSO4 was added and the resulting mixture was extracted with DCM (50 mL×3). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give 3-methyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester (103 mg), m/z=277.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[N:8]([C:9](=C(C)C)[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2].[O:29]=[O+][O-].O=O>CO.C(Cl)Cl>[C:1]([O:4][C@@H:5]1[N:8]([C:9](=[O:29])[C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:17])[C@H:6]1[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])(=[O:3])[CH3:2]
Reactant: O=[O+][O-]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O
Agent: O=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C(=O)N1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@@H]1OC(C)=O

Procedure:
Into a solution of 970 mg (2.5 mmol) methyl 2-((3S,4S)-4-acetoxy-3-benzyloxycarbonylaminoazetidin-2-on-1-yl)-3-methylbut-2-enoate in 40 ml of methanol, at -10° C., for 120 minutes a mixture of ozone and oxygen is introduced at a rate of 0.1 mmol per minute. The clear solution is diluted with 60 ml of methylene chloride and the mixture subsequently washed with 50 ml of aqueous sodium bisulfite solution (10%) and 100 ml of saturated sodium chloride solution. After drying of the organic layer over sodium sulfate, filtration and evaporation of the filtrate in vacuo 780 mg of a noncrystalline solid is obtained (86%) (title compound). IR spectrum in methylene chloride: 3400, 1835, 1755, 1720 and 1510 cm-1.
Reaction SMILES: [O:1]1[C:3]2([CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]2)[CH2:2]1.[CH2:13]([NH2:15])[CH3:14]>>[CH2:13]([NH:15][CH2:2][C:3]1([OH:1])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4]1)[CH3:14]
Reactant: CCOC(=O)N1CCC2(CO2)C1
Reactant: CCN
Product: CCNCC1(O)CCN(C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8 g (46.7 mmol) of ethyl 5-aza-1-oxaspiro[2,4]heptane-5-carboxylate are added dropwise to 50 ml of ethylamine solution (50% in water) and the mixture is stirred overnight at room temperature. It is concentrated and the residue is distilled.