Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[CH:41]1[O:54][CH2:53][C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@@H:43]([O:44][C:45](=[O:47])[CH3:46])[CH2:42]1)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:1][C:2]1[N:3]([C@H:41]2[O:54][CH2:53][C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@@H:43]([O:44][C:45](=[O:47])[CH3:46])[CH2:42]2)[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1cc2nc(Br)[nH]c2cc1Cl
Reactant: CC(=O)OC1C[C@H](OC(C)=O)[C@H](OC(C)=O)CO1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCCl
Product: CC(=O)O[C@H]1C[C@@H](n2c(Br)nc3cc(Cl)c(Cl)cc32)OC[C@H]1OC(C)=O
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
As described in General Procedure III, 2-bromo-5,6-dichlorobenzimidazole (0.52 g, 2.0 mmol), N,O-bis(trimethylsilyl) acetamide (Aldrich, 0.53 ml, 2.2 mmol), and 1,2-dichloroethane (Aldrich Sure Seal, 20 ml) were combined and refluxed under nitrogen for 0.25 h. The solution was cooled to 50° C. and trimethylsilyl trifluoromethanesulfonate (Aldrich, 0.42 ml, 2.2 mmol) was added. Immediately, 0.51 g (2.0 mmol) solid 1,3,4-tri-O-acetyl-2-deoxy-D-erythro-pentopyranose (as prepared and described by R. Allerton and W. G. Overend in J. Chem. Soc. 1951, 1480-1484) was added. The solution was stirred under nitrogen at 50° C. for 0.5 h, then poured into 7% aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried with magnesium sulfate (anhyd), filtered, and evaporated. The crude residue was purified on a silica gel column eluting with a step gradient of 0.1% to 1% methanol in dichloromethane to give 0.47 g (1.0 mmol, 52% yield) 2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-alpha-D-erythro-pentopyranosyl)-1H-benzimidazole; 1H NMR (CD3OD) δ8.11 (s, 1H), 7.80 (s, 1H), 6.11-6.07 (dd, 1H), 5.37-5.32 (m, 2H), 4.24-4.19 (dd, 1H), 4.05-4.00 (dd, 1H), 2.68-2.56 (q, 1H), 2.32 (s, 3H), 2.20-2.15 (m, 1H), 2.01 (s, 3H); and 0.13 g (0.28 mmol, 14% yield) 2-bromo-5,6-dichloro-1-(3,4-di-O-acetyl-2-deoxy-beta-D-erythro-pentopyranosyly)-1H-benzimidazole; 1H NMR (CD3OD) δ8.02 (s, 1H), 7.76 (s, 1H), 6.13-6.10 (d, 1H), 5.62 (bs, 1H), 5.29-5.23 (m, 1H), 4.15-4.03 (m, 2H), 2.76-2.70 (t, 1H), 2.19 (s, 3H), 2.15-2.1 (m, 1H), 2.00 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:6][OH:7])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:7][CH2:6][CH:5]([NH:8][C:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:15])[CH2:4][O:3][CH2:1][CH3:2])(=[O:19])=[O:18]
Reactant: CCOCC(CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCOCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of tert-butyl (1-ethoxy-3-hydroxypropan-2-yl)carbamate (2.2 g, 9.4 mmol) in DCM (40 mL) was added methanesulfonylchloride (2.10 g, 18.8 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 12 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified via chromatography on silica gel to afford 2-[(tert-butoxycarbonyl)amino]-3-ethoxypropyl methanesulfonate. MS ESI calc'd. for C11H24NO6S [M+H]+ 298. found 298. 1H NMR (400 MHz, CDCl3) δ 4.95 (s, 1H), 4.28 (d, J=8.0 Hz, 1H), 4.13-4.11 (m, 1H), 3.58-3.48 (m, 5H), 3.03 (s, 3H), 1.45 (s, 9H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:4]([OH:6])=O.Cl.[NH:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:11]([O:10][C:8](=[O:9])[NH:7][C@@H:3]([C:4]([N:16]1[CH2:19][CH:18]([C:20]#[N:21])[CH2:17]1)=[O:6])[CH2:2][CH3:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#CC1CNC1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.9 %

Procedure:
In a round-bottomed flask Boc-D-2-aminobutyric acid (400 mg, 1.97 mmol) and azetidine-3-carbonitrile hydrochloride (373 mg, 3.15 mmol) were dissolved in DMF (9 ml). N,N-Diisopropylethylamine (1.0 ml, 5.73 mmol) was added followed by HATU (823 mg, 2.16 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to provide 410 mg (70%) of [(R)-1-(3-cyano-azetidine-1-carbonyl)-propyl]-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: O=[CH:2][CH2:3][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH3:5].[C:14]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[C:9]([O:8][C:7]([NH:6][C@H:4]([CH3:5])[CH2:3]/[CH:2]=[CH:19]/[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@H](CC=O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.4 %

Procedure:
To a solution of (R)-tert-butyl 4-oxobutan-2-ylcarbamate (1.54 g, 8.22 mmol) in THF (25 mL) at rt was added (carbethoxymethylene)triphenylphosphorane (6.30 g, 18.1 mmol) in portions. The resulting clear solution was stirred at rt under argon for 3 days. The reaction mixture was concentrated and the oily residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-60% EtOAc/Hex to give (R,E)-ethyl 5-(tert-butoxycarbonylamino)hex-2-enoate (1.70 g, 6.61 mmol, 80% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 6.91 (dt, J=15.3, 7.5 Hz, 1H), 5.92-5.82 (m, 1H), 4.37 (s, 1H), 4.19 (q, J=7.1 Hz, 2H), 3.83 (s, 1H), 2.37 (t, J=6.6 Hz, 2H), 1.44 (s, 9H), 1.29 (t, J=7.1 Hz, 3H), 1.15 (d, J=6.7 Hz, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH:20]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:18][CH2:19][CH2:20][N:33]2[CH2:34][CH2:35][N:30]([C:27]3[CH:26]=[CH:25][C:24]([O:23][CH3:22])=[CH:29][CH:28]=3)[CH2:31][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cc(CCCN3CCN(c4ccc(OC)cc4)CC3)nn2C(C)(C)C)cc1

Procedure:
107 mg (73%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-methoxyphenyl)-1H-pyrazol-3-yl)propanal (85 mg, 0.297 mmol), 1-(4-methoxyphenyl)piperazine (57 mg, 0.297 mmol), DIPEA (0.078 mL, 0.446 mmol) and NaBH(OAc)3 (189 mg, 0.891 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][OH:17]>CN(C=O)C.O>[OH:17][CH2:16][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: OCCBr
Reactant: COc1cc(O)ccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OCCO)ccc1C=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-hydroxy-2-methoxybenzaldehyde (1.217 g, 8.00 mmol) in dry DMF (8.88 mL) was added to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (0.267 mL, 8.00 mmol) in dry DMF (2.22 mL) via cannula at 0° C. under N2. The reaction mixture was stirred at 0° C. for 30 min and warmed to room temperature. 2-bromoethanol (0.851 mL, 12.00 mmol) was added dropwise and the reaction mixture was stirred at 50° C. overnight. The reaction was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined extracts were washed with 1N aq. NaOH (50 mL), dried (MgSO4) and concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 40M, Si, ˜30 mL/min, 100% hexanes for 360 mL, gradient to 60% EtOAc in hexanes over 4536 mL) to afford 4-(2-hydroxyethoxy)-2-methoxybenzaidehyde, as a colorless solid. Rf=0.29 (50% EtOAc/hexanes). LCMS calc.=197.1; found=197.0 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 10.16 (s, 1 H); 7.68 (d, J=8.7 Hz, 1 H); 6.46 (dd, J=8.7, 2.2 Hz, 1 H); 6.40 (d, J=2.2 Hz, 1 H); 4.09 (t, J=4,6 Hz, 2 H); 3.94 (t, J=4.4 Hz, 2 H); 3.79 (s, 3 H); 3.20 (s, 1 H).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27](O)(=[O:29])[CH3:28]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, off-white solid (33 mg, 48%), MS (ISP) m/z=371.4 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (75 mg, 0.19 mmol) and acetic acid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][CH:6]([C:12](OCC)=[O:13])[C:7](OCC)=[O:8].C[O-].[Na+]>CCO>[SH:3][C:2]1[N:4]=[C:7]([OH:8])[C:6]([CH3:5])=[C:12]([OH:13])[N:1]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: NC(N)=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)nc(S)nc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of thiourea (1 g, 13.14 mmol) and diethyl methylmalonate (3.4 mL, 19.71 mmol) in EtOH (15 mL), NaOMe (2.68 g, 39.41 mmol) was added portionwise. After stirring at 0° C. for 30 min, the reaction was allowed to reach rt and was stirred for another 3 h at rt. The mixture was quenched with diluted acetic acid and the solid was filtered off to yield 2-mercapto-5-methylpyrimidine-4,6-diol as a white solid which was used in the next step without further purification. LC-MS conditions A: tR=0.21 min, [M+H]+=159.11.
Reaction SMILES: [CH2:1](C(CC)(CC)C([O-])([O-])[O-])[CH3:2].[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[N:33]=[CH:32][C:31]([C:34]([NH:36][NH2:37])=[O:35])=[CH:30][CH:29]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:16]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:25]([O:27][C:28]4[CH:29]=[CH:30][C:31]([C:34]5[O:35][C:1]([CH3:2])=[N:37][N:36]=5)=[CH:32][N:33]=4)=[CH:26][C:19]=3[CH2:18][CH2:17]2)[CH2:13][CH2:14][CH2:15]1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: NNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)nc1
Product: Cc1nnc(-c2ccc(Oc3ccc4c(c3)CCN(C3CCC3)CC4)nc2)o1

Procedure:
A mixture of triethylorthoacetate (3 ml) and 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinecarbohydrazide (D54) (185 mg, 0.52 mmol) was heated at reflux for 16 hours. The reaction mixture was concentrated and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:methanol:dichloromethane (0.1:5:95) to afford the title compound (E216). MS (ES+) m/e 377 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:14]1([C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:23]=[C:22](NC(NC3C=CC=C(C(F)(F)F)C=3)=O)[CH:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[N:23]=[C:22]([CH2:3][CH2:4][CH2:5][NH:9][C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)=[O:11])[CH:21]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NS(=O)(=O)c1ccc(-n2nc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: NS(=O)(=O)c1ccc(-n2nc(CCCNC(=O)Nc3cccc(C(F)(F)F)c3)cc2-c2ccccc2)cc1
Yield: 84 %

Procedure:
The titled compound was prepared in 84% yield from 3-(trifluoromethyl)phenyl isocyanate using the procedure detailed for compound 7. mp 175.5-176.4° C. 1H NMR (300 MHz, DMSO-d6): δ 8.85 (s, 1H), 7.98 (s, 1H), 7.79 (d, J=9 Hz, 2H), 7.53-7.35 (m, 9H), 7.29-7.18 (m, 3H), 6.57 (s, 1H), 6.38 (t, J=6 Hz, 1H), 3.25-3.17 (m, 2H), 2.69 (t, J=8 Hz, 2H), 1.94-1.80 (m, 2H). MS (ESI) m/z: 544.16 (M+H+). Anal. Calcd for C26H24F3N5O3S: C, 57.45; H, 4.45; N, 12.88. Found: C, 57.31; H, 4.46; N, 12.74.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[N:5]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH:17]=O)[CH:3]=1.Cl.[C:20]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:33]2[CH2:32][CH2:31][N:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[CH2:35][CH2:34]2)[N:5]=[C:6]2[C:11]=1[CH2:10][CH2:9][C:8](=[O:12])[NH:7]2
Reactant: Cc1cc(OCCCC=O)nc2c1CCC(=O)N2
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: Cl
Product: Cc1cc(OCCCCN2CCN(c3cccc4ccccc34)CC2)nc2c1CCC(=O)N2

Procedure:
The title compound was prepared by reductive amination of 4-(4-methyl-7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde with 1-naphthalen-1-yl-piperazine hydrochloride according to the above procedure. MS: APCI: M+1: 445.2 (Exact Mass: 444.25).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[C@:6]3([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=2[CH:3]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]3.[N+:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)([O-:20])=[O:19].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+:18]([C:21]1[CH:26]=[C:25]([C:2]2[CH:17]=[CH:16][C:5]3[C@:6]4([CH3:15])[C@@H:11]([CH2:12][CH2:13][C:4]=3[CH:3]=2)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]4)[CH:24]=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(Br)ccc12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cccc([N+](=O)[O-])c3)ccc12
Yield: 79.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (500 mg, 1.70 mmol), tetrakis(triphenylphosphine) palladium (0) (80 mg, 0.07 mmol), 3-nitrophenylboronic acid (426 mg, 2.55 mmol), 2.4 mL of 2M sodium carbonate and 4 mL of toluene, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (200 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 456 mg (80%) of the title compound as a white solid. mp 223°-225°. FDMS: m/e=336. α[D]589 =+45.63 (c=1.03, methanol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=S)[CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10](=[N:19][NH2:20])[C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[CH:3]=1
Reactant: Cc1cc(C)nc(NC(=S)c2cnccn2)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(C)nc(NC(=NN)c2cnccn2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1 g of compound of Example 24 dissolved in 30 ml of ethanol is added 0.6 ml of hydrazine monohydrate and the mixture is left stirring for 30 minutes at room temperature. The reaction medium is then poured into ice-water. It is stirred vigorously for 20 minutes. The mixture is filtered and dried and the residue is recrystallized from isopropyl ether.
Reaction SMILES: CO[C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl>O>[NH:16]([C:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[C:5](=[O:15])[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Product: O=c1[nH]c2ccccc2c(=O)cc1Nc1ccccc1

Procedure:
3-Methoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (1.0 g) and aniline (10 mL) were heated to reflux for 5 hours and diluted with water. Hydrochloric acid (2N) was added and the mixture extracted with ethyl acetate. The organic extracts were washed (acid, brine), dried and evaporated to give a solid which was purified by chromatography, with ethyl acetate:toluene (1:4) as the eluent. Recrystallization from ethyl acetate gave the title compound (0.405 g); mp 227°-228° C.: NMR: 6.28 (s,1); MS(E1): m/z=264(M). Analysis for C16H12N2O2 ·0.1 H2O: Calculated: C, 72.22; H, 4.62; N, 10.53; Found: C, 72.32; H, 4.68; N, 10.65.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:27])[CH:25]=[O:26])[CH3:22]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:21]([O:23][C:24](=[O:27])[CH:25]([OH:26])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH3:22]
Reactant: CCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-pentan-2-one (2.98 mmol, 11.4 g), oxo-acetic acid ethyl ester solution in toluene (8 mL, 50% solution in toluene) and triethylamine (2 mL) was stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure, and the resultant residue was purified by flash silica gel chromatography using by eluting with 30% ethyl acetate in hexanes to provide 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-heptanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-:14].[Cs+]>C(OCC)(=O)C.CCCCCCC>[C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:7][C:2]([OH:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Oc1ccc(-c2ccccc2)cc1
Yield: 90 %

Procedure:
Following general operating mode B, 4-bromobiphenyl (232 mg, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a brown solid with a yield of 90% (eluent: ethyl acetate/heptane 20:80).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.CCN(CC)CC.[S:24](Cl)([C:27]1[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=1)(=[O:26])=[O:25].[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:31][C:30]1[CH:32]=[CH:33][C:27]([S:24]([O:1][CH2:2][CH:3]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)(=[O:26])=[O:25])=[CH:28][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)NC(CO)c1ccsc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC(NC(=O)OC(C)(C)C)c2ccsc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To tert-butyl 2-hydroxy-1-(thiophen-3-yl)ethylcarbamate (E1) in CH2Cl2 was added NEt3, DMAP, and TsCl. The solution was stirred at room temperature for 3 hours and then poured into NH4Cl (sat) and extracted with EtOAc, dried (Na2SO4), filtered, and evaporated. Column chromatography (SiO2, 30% EtOAc/Hexanes) gave pure 2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)ethyl 4-methylbenzenesulfonate (E2).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]([C:31](O)=[O:32])=[CH:23][N:22]=3)[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CN.C1C=CC2N(O)N=[N:42][C:40]=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:16][CH2:17][N:18]([C:21]3[N:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[C:24]([C:31](=[O:32])[NH:42][CH3:40])=[CH:23][N:22]=3)[CH2:19][CH2:20]2)[CH2:11][CH2:12]1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3ncc(C(=O)O)c(C(F)(F)F)n3)CC2)CC1
Reactant: On1nnc2ccccc21
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1cnc(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Half of the crude 57b was combined with methylamine (0.06 mmol), HOBT (7 mg, 0.06 mmol) and EDC(10 mg, 0.05 mmol) in 1 mL of DCM. The mixture was stirred at room temperature for 18 h, washed with aqueous NaHCO3 and concentrated. The residue was purified by preparative HPLC to afford 57-1: LC-MS 487.3 (MH+), tR=5.20 (Method 5).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:30]>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1
Reactant: Clc1ccccc1Br
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(c1ccccc1Cl)CC2

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 1 step C) and 2-bromoclorobenzene. Light yellow solid. MS (ESI): 425.1 (MH+)
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][NH:27]2)=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][CH2:26][N:27]2[C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)=[CH:23][CH:22]=1
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Fc1ccc2c(c1)NCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)N2CCc3ccc(F)cc32)nc(N2CCOCC2)cc1=O
Yield: 37.6 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 205 mg of 6-fluoroindoline and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 140 mg of 2-[2-(6-fluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a very pale pink powder, the characteristics of which are the following: