Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:30])[C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[F:31][CH:32]([F:42])[C:33]1[N:34]=[CH:35][C:36]([C:39](O)=[O:40])=[N:37][CH:38]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:20])([F:19])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:39]([C:36]3[CH:35]=[N:34][C:33]([CH:32]([F:42])[F:31])=[CH:38][N:37]=3)=[O:40])[CH:3]=[C:4]([F:30])[C:5]=2[F:29])[N:9]=1
Reactant: O=C(O)c1cnc(C(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Product: NC1=N[C@@]2(c3cc(NC(=O)c4cnc(C(F)F)cn4)cc(F)c3F)CO[C@H](C(F)(F)F)[C@H]2CS1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-difluoromethyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.90 (dd, J=13.8, 3.7 Hz, 1H), 3.19 (dd, J=13.8, 2.7 Hz, 1H), 3.31-3.49 (m, 1H), 3.95 (d, J=7.6 Hz, 1H), 4.44-5.15 (m, 4H), 6.81 (t, J=55.8 Hz, 4H), 7.22-7.35 (m, 1H), 8.08 (ddd, J=11.2, 6.8, 2.7 Hz, 1H), 8.94 (s, 1H), 9.53 (s, 1H), 9.67 (s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6]2.[H-].[Na+].Br[CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26].ClCCl.CCCCCC>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])[C:7]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[CH:6]2
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: COc1ccc2[nH]c(-c3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cccc(Cn2c(-c3ccccc3)cc3cc(OC)ccc32)c1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 41.7 %

Procedure:
To a solution of 5-methoxy-2-phenylindole (73.0 mg) in N,N-dimethylformamide (1.6 mL) was added sodium hydride (dispersed in liquid paraffin, minimum 55%, 22 mg) under cooling with ice, and the mixture was stirred at room temperature for 70 minutes. Then methyl 3-(bromomethyl)benzoate (89.9 mg) was added, and the mixture was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature. Saturated ammonium chloride-water (2/1) were added and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by aminopropylated silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (50.6 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([SH:16])[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=2)[CH2:27]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]([CH3:15])=[C:11]([S:16][CH2:27][C:26]2[CH:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:31]=[CH:30][CH:29]=2)[NH:10][C:9]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(S)[nH]c(=O)n(Cc2ccccc2)c1=O
Reactant: BrCc1cccc(-c2ccccc2)c1
Solvent: CN(C)C=O
Product: Cc1c(SCc2cccc(-c3ccccc3)c2)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 60 °C
Yield: 98.9 %

Procedure:
3-Benzyl-6-mercapto-5-methyl-1H-pyrimidine-2,4-dione (0.25 g, 1.0 mmol) was dissolved in dimethylformamide (10 mL). 3-Phenylbenzyl bromide (0.25 g, 1.02 mmol) was added and the reaction heated at 60° C. for 2 hours. The dimethylformamide was removed in vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (3:1) to give 3-benzyl-6-(biphenyl-3-ylmethylsulfanyl)-5-methyl-1H-pyrimidine-2,4-dione (0.41 g, 99% yield). MS (APCI+), m/z (%): 415(100), 413 (30), 247(100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].C[O:12][C:13]1C=CC=C(N)[CH:14]=1>>[NH2:5][C:4]1[CH:3]=[C:2]([Cl:1])[C:8]([O:9][CH3:10])=[CH:7][C:6]=1[C:13](=[O:12])[CH3:14]
Reactant: COc1cccc(N)c1
Reactant: COc1ccc(N)cc1Cl
Product: COc1cc(C(C)=O)c(N)cc1Cl
Yield: 50 %

Procedure:
1-(2-Amino-4-chloro-5-methoxy-phenyl)-ethanone 201g was synthesized from 3-chloro-4-methoxy-aniline 215g as a brown solid in 50% yield, according to the procedure as described for compound 215a. MS (ESI, EI+): m/z=200 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)(C(OC)=O)[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Na+].C(OCC)(=O)C>CN1C(=O)CCC1.O>[CH3:1][O:2][CH:3]([CH2:12][C:13]1[N:14]=[CH:15][N:16]([C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)(OC)C(=O)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OC
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of dimethyl 2-methoxy-2-((1-trityl-1H-imidazol-4-yl)methyl)malonate (0.1520 g, 0.31 mmol) and sodium chloride (0.0398 g, 0.68 mmol) in NMP (2 mL) and water (0.3 mL) was heated to 201° C. for 1 hr. After cooling to room temperature, ethyl acetate (15 mL) was added and the organic layer was washed with water (2×10 mL), saturated sodium chloride (1×10 mL) and then dried over NaSO4. Solvent removal yielded 0.1030 g of crude product. This was purified by chromatography on a silica gel 60 (11 g, 0.040 to 0.063 mm particle size) column (2.5×10 cm) using CHCl3/MeOH (98:2) as the eluent and collecting 12 mL fractions. Fractions 2 to 10 were pooled and dried, and the residue was re-purified as above, except that 5 g of silica gel was used and the eluent was CHCl3/MeOH (99:1). Fractions 10 to 16 were pooled and afforded, after drying, 0.0592 g (45%) of 94.5% pure methyl 2-methoxy-3-(1-trityl-1H-imidazol-4-yl)propanoate; retention time, 7.29 min.; column: YMC ODS-A (3 μm, 50×4.6 mm); gradient: 10% to 100% B in A over 10 min. at 1.25 mL/min. Solvent A: 0.1% TFA in water, Solvent B: 0.1% TFA in AcCN. LC/MS: ESI (M+H)+=427.1.
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.[O:23]=[C:24](Cl)OC(Cl)(Cl)Cl.[CH2:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=1)[CH3:32]>>[CH2:31]([N:33]([C:34]1[CH:35]=[CH:36][C:37]([O:40][C:41]([F:42])([F:43])[F:44])=[CH:38][CH:39]=1)[C:24]([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)=[O:23])[CH3:32]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: CCNc1ccc(OC(F)(F)F)cc1
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1ccc(OC(F)(F)F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-(4-trifluoromethoxy-phenyl)-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 546.5 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:42]1[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=1>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][C:15]([O:21][CH2:22][C:23]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:25][N:26]([C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=4)[CH2:27][CH2:28]3)=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(Cl)cc(C)n1
Reactant: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCNCC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)CCN(c2cc(C)nc(C)c2)CC1
Temperature: 150 °C
Reaction time: 25 h
Yield: 92.7 %

Procedure:
To a solution of 7-(4-ethoxycarbonylpiperidin-4-ylmethoxy)-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid benzyl ester (140 mg) in ethanol (3 ml) were added triethylamine (0.05 ml) and 4-chloro-2,6-dimethylpyridine (Journal of Heterocyclic Chemistry, vol. 27, p. 1841 (1990)) (45 mg) and the mixture was stirred at 150° C. for 25 hours in a sealed tube. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=4:1) and dried under reduced pressure to give the title compound (160 mg).
Reaction SMILES: C1CCNCC1.[CH:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:39]=[CH:38][C:24]([CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([CH2:32][NH:33][C:34](=[O:37])[CH2:35][NH2:36])[CH2:28][CH2:27]2)=[CH:23][CH:22]=1>C(Cl)(Cl)Cl>[Cl:20][C:21]1[CH:39]=[CH:38][C:24]([CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([CH2:32][NH:33][C:34](=[O:37])[CH2:35][NH:36][S:16]([C:13]3[CH:14]=[CH:15][C:10]([CH:7]([CH3:9])[CH3:8])=[CH:11][CH:12]=3)(=[O:18])=[O:17])[CH2:30][CH2:31]2)=[CH:23][CH:22]=1
Reactant: NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCNCC1
Product: CC(C)c1ccc(S(=O)(=O)NCC(=O)NCC2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A (piperidinomethyl)polystyrene resin (28 mg, 2.8 mmol/g) and 4-isopropylbenzenesulfonyl chloride (1.5 equivalents) were added to a chloroform (2 mL) solution of 1-(4-chlorobenzyl)-4-[(glycylamino)methyl]piperidine (14.8 mg, 0.05 mmol). The resulting mixture was stirred at 25° C. for 16 hours, then filtered and concentrated to thereby afford 1-(4-chlorobenzyl)-4-[[N-(4-isopropylphenylsulfonyl)glycyl]aminomethyl]piperidine (Compd. No. 869) (22.1 mg, 92%). The purity was determined by RPLC/MS (86%). ESI/MS m/e 478 (M++H, C24H32N3O3S).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:31])[CH:11]([NH:23]C(OC(C)(C)C)=O)[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.ClCCl.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>C(Cl)(Cl)(Cl)Cl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH2:15]([NH:14][C:12](=[O:13])[CH:11]([NH2:23])[C:10]([NH:9][CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:31])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reaction time: 2.5 h
Yield: 100 %

Procedure:
Combine N,N′-diphenethyl-2-(t-butoxycarbonylamino)malonamide (0.571 g, 1.35 mmol) and dichloromethane (10 mL). Add trifluoroacetic acid (1.8 mL). After 2.5 hours, evaporate in vacuo to give a residue. Add hexanes and carbon tetrachloride to co-evaporate residual trifluoroacetic acid and evaporate in vacuo to give the title compound (100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])[C@@H:7]([CH3:18])[CH2:6][NH:5]2.C(N(CC)C(C)C)(C)C.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:17])[C:13]([F:14])([F:16])[F:15])[C@@H:7]([CH3:18])[CH2:6][N:5]2[C:33]([C:29]1[O:28][CH:32]=[CH:31][CH:30]=1)=[O:34]
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C(F)(F)F
Reactant: O=C(Cl)c1ccco1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)c2ccco2)c2cc(Br)ccc2N1C(=O)C(F)(F)F
Reaction time: 0.08 h
Yield: 53.8 %

Procedure:
A 100 mL round bottomed flask fitted with a nitrogen inlet was charged with (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (1.54 g, 4.77 mmol), 1,2-dichloroethane (45 mL), and N,N-diisopropylethyl amine (2.497 mL, 14.30 mmol). The mixture stirred for 5 min and then furan-2-carbonyl chloride (0.940 mL, 9.53 mmol) was slowly added. The reaction stirred at room temperature for 2 h and was then concentrated. The residue was purified via column chromatography (eluting with 3:2 hexanes/ethyl acetate) to afford (S)-1-(6-bromo-4-(furan-2-carbonyl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)-2,2,2-trifluoroethanone (1.07 g, 54%) as an off-white solid. MS (ESI, pos. ion) m/z 417, 419 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].O>ClCCl>[CH3:42][S:43]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:45])=[O:44]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(C)(=O)=O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 38.7 %

Procedure:
4-Hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.230 g, 0.498 mmol) was dissolved in dichloromethane (4.6 mL), and the solution was added with triethylamine (0.139 mL, 0.997 mmol) and methanesulfonyl chloride (0.0460 mL, 0.598 mmol), followed by stirring under ice-cooling for 1.5 hours. The reaction mixture was added with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-methanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.104 g, yield 61%).
Reaction SMILES: [OH:1][C:2]1([CH2:6][S:7]([NH2:10])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH:21]1([N:27]=[C:28]=S)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.BrN1C(=O)CCC1=O>CN1C(=O)CCC1.C1COCC1.O>[CH:21]1([NH:27][C:28]2[O:1][C:2]3([CH2:6][S:7](=[O:9])(=[O:8])[N:10]=2)[CH2:5][CH2:4][CH2:3]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: S=C=NC1CCCCC1
Reactant: NS(=O)(=O)CC1(O)CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN1CCCC1=O
Product: O=S1(=O)CC2(CCC2)OC(NC2CCCCC2)=N1
Reaction time: 0.67 h

Procedure:
Under inert gas, 200 mg of (1-hydroxycyclobutyl)methanesulfonamide were dissolved in 2.5 ml of NMP, and admixed at −10° C. with 0.61 ml of a 2 N solution of sodium bis(trimethylsilyl)amide in THF and, after stirring for 5 minutes, with a solution of 0.19 ml of cyclohexyl isothiocyanate in 0.5 ml of NMP. After stirring at constant temperature for 40 minutes, 215 mg of N-bromosuccinimide were added in 4 portions within 5 minutes, and the reaction solution was stirred for a further 15 minutes. The reaction mixture was diluted with 60 ml of water and extracted twice with 20 ml of ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over MgSO4 and concentrated by rotary evaporation. The residue was purified in a purification laboratory by means of preparative HPLC. After lyophilization of the product-containing fractions, the product (114.7 mg) was thus obtained with a molecular weight of 272.4 g/mol (C12H20N2O3S); MS (ESI): m/e=273 (M+H+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH2:12]1[C:17]2[NH:18][C:19]3[C:24]([C:16]=2[CH2:15][CH2:14][NH:13]1)=[CH:23][CH:22]=[CH:21][CH:20]=3.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH2:5]([O:4][C:2]([N:13]1[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH2:12]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl chloroformate (1.8 ml, 12.6 mmol) was added to a solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (1.72 g, 10.0 mmol) and sodium bicarbonate (1.85 g, 22.0 mmol) in dioxan (50 ml) at room temperature. The mixture was stirred at room temperature for 16 hours, concentrated in vacuo and the residue dissolved in water (50 ml). The aqueous mixture was extracted with chloroform (3×50 ml), and the combined extracts dried (MgSO4). Filtration and evaporation of the solvent gave the crude product which was purified by chromatography on silica gel with hexane-ethyl acetate (3:2) as eluant. (3.07 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[N:6]=1.C(O)(=O)/C=C\C(O)=O.C(N[CH:26]=[N:27][C:28]1[CH:33]=[CH:32][C:31](C2N=C(C)NC=2)=[CH:30][C:29]=1OC)CC>>[C:28]1([NH:27][CH:26]=[N:13][C:10]2[CH:11]=[CH:12][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[CH:8][CH:9]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1nc(-c2ccc(N)cc2)c[nH]1
Reactant: CCCNC=Nc1ccc(-c2c[nH]c(C)n2)cc1OC
Agent: O=C(O)/C=C\C(=O)O
Product: Cc1nc(-c2ccc(N=CNc3ccccc3)cc2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Methyl-4-(4-amino-phenyl)-1H-imidazole (5 g) was added to a solution of ethyl N-phenyl-formamidate (5 g) in acetone (25 ml). After 3 hours of stirring at room temperature, the solid which separated out was filtered off and dried. The product was treated with glacial acetic acid in acetone. The acetate salt which precipitated was filtered off and dried to give 4.6 g of the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:9]1([C:15](=O)[CH2:16][CH2:17][C:18](=O)[CH3:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C.C(Cl)Cl>[CH3:19][C:18]1[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)Cn1c(C)ccc1-c1ccccc1
Temperature: 70 °C
Yield: 72.5 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (1.378 g, 9.87 mmol) was diluted with ethanol (50 ml) then charged with TEA (8 ml, 57.4 mmol). 1-Phenylpentane-1,4-dione (1.74 g, 9.87 mmol) was then added and reaction was heated at 70° C. overnight. The reaction mixture was then diluted with 100 mL DCM and washed with water (100 mL). The aqueous was back-extracted with DCM (50 mL×2), the organics were combined, dried (Na2SO4), filtered, and concentrated to yield a crude orange oil. This oil was loaded onto a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording 1.74 g (72.4% yield) of the desired ethyl 2-(2-methyl-5-phenyl-1H-pyrrol-1-yl)acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl.[Cl:10][CH2:11][C:12](=N)OC>C(Cl)Cl>[Cl:10][CH2:11][C:12]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: COC(=N)CCl
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: ClCCl
Product: ClCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of aminothiophenol (8.3 g) in methylene chloride at 0° C. is added methyl chloroacetimidate hydrochloride [prepared according to procedures described by R. Rogers and D. G. Nielson, Chem. Rev., 61, 179 (1961)] (8.6 g). The reaction is allowed to warm to room temperature while stirring overnight. The mixture is washed with water (3X); dried over magnesium sulfate and concentrated to an oil. The oil is distilled (120°-135° C. at 0.5 mm Hg) to give 7.8 g (71% yield) of product.
Reaction SMILES: I[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[O:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].CCN(C(C)C)C(C)C>CCO>[OH:14][C@:15]1([CH3:30])[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[O:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: O=[N+]([O-])c1cnc2c(c1I)CCO2
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@]1(C)O
Temperature: 110 °C
Reaction time: 15 h
Yield: 65.7 %

Procedure:
To a vial containing 4-iodo-5-nitro-2,3-dihydrofuro[2,3-b]pyridine (59 mg, 0.20 mmol) and tert-butyl [(3R,4R,5S)-4-hydroxy-4,5-dimethylpiperidin-3-yl]carbamate (46 mg, 0.19 mmol) was added EtOH (2.0 mL), followed by DIPEA (100 mg, 0.772 mmol). The mixture was stirred at 110° C. for 15 h. After cooling to the room temperature, the reaction was concentrated under reduced pressure. The resulting residue was purified on silica gel (0-100% EtOAc in hexanes) to give the sub-title compound as a yellow foamy solid (51 mg, 67%). LCMS calc. for C19H29N4O6 (M+H)+: m/z=409.2. found 409.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[CH3:13].[Mn]([O-])(=O)(=O)=[O:15].[K+].N1C=CC=CC=1.[OH2:26]>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[C:13]([OH:15])=[O:26]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cc(C)c(Cl)cc1[N+](=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: COc1cc(C(=O)O)c(Cl)cc1[N+](=O)[O-]
Temperature: 97 °C

Procedure:
A suspension of 1-chloro-4-methoxy-2-methyl-5-nitro-benzene (1.05 g, 5.21 mmol) in a mixture of pyridine and water (1/2, 15 mL) was heated to 97° C. and then potassium permanganate (4.53 g, 28.64 mmol) was added. The reaction mixture was heated at 100° C. for 4 hours; a second aliquot of the mixture pyridine/water (1/1, 10 mL) was added and was followed by potassium permanganate (1 g); the resulting mixture was heated to 100° C. overnight. The hot reaction mixture was filtered through a CELITE™ pad, the filter cake was washed with hot water and the filtrate was acidified, until pH 1, by addition of an aqueous solution of hydrochloric acid (6 M). The resulting mixture was extracted with ethyl acetate; the organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The light yellow solid residue (903 mg) was washed twice with a small aliquot of dichloromethane to give 2-chloro-5-methoxy-4-nitro-benzoic acid as an off-white solid without further purifications.
Reaction SMILES: Br[CH:2]([CH3:10])[C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:11][C:12]([NH2:14])=[S:13]>>[NH2:14][C:12]1[S:13][C:2]([CH3:10])=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:11]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(=O)C(C)Br
Product: CCOC(=O)c1nc(N)sc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.4 %

Procedure:
Ethyl 3-bromo-2-oxobutanoate (Intermediate 177, 12.2 g; 58.7 mmol) and thiourea (4.46 g; 76.1; 58.7 mmol) were combined and heated to reflux. The solution was allowed to cool to room temperature and stir for 12 hours. The reaction was monitored by LC/MS. The base was precipitated with 20% NH4OH (10 ml) and then redissolved with 1N HCl (100 ml) and then finally reprecipitated with 20% NH4OH. The precipitate was collected and washed with H2O. The crude product was then crystallized from 9:1 ethanol/water to give 5.95 g of product in 55% yield. MS (ES) MH+: 187 for C7H10N2O2S.