Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[C:20]2[CH:19]=[CH:18][C:17]([Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Si:31]([CH:38]([CH3:40])[CH3:39])([CH:35]([CH3:37])[CH3:36])[CH:32]([CH3:34])[CH3:33])[CH:13]=2)C1C=CC=CC=1.C1COCC1.O=O>CS(C)=O>[CH:38]([Si:31]([CH:32]([CH3:34])[CH3:33])([CH:35]([CH3:37])[CH3:36])[C:12]1[CH:11]=[CH:10][C:9]2[NH:8][C:20]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][C:17]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])=[CH:18][CH:19]=3)([CH3:40])[CH3:39]
Reactant: CC(C)[Si](c1ccc2c(c1)c1cc([Si](C(C)C)(C(C)C)C(C)C)ccc1n2Cc1ccccc1)(C(C)C)C(C)C
Agent: O=O
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)[Si](c1ccc2[nH]c3ccc([Si](C(C)C)(C(C)C)C(C)C)cc3c2c1)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 52.1 %

Procedure:
A 500 ml dry round bottom flask was charged with 9-benzyl-3,6-bis-triisopropylsilanyl-9H-carbazole 4 (23.0 g, 0.04 mol) and the oil was suspended in 100 ml DMSO. The suspension was cooled in an ice water bath (˜15° C.) and 1M KOBu-t in THF (240 ml, 0.24 mol) was added via a syringe under nitrogen. Oxygen started to bubble in the mixture and the nitrogen line was suppressed. While the oxygen bubbling was taking place, the mixture was left to warm up to ˜20° C. and cooling continued with only water. The oxygen bubbling continued until the starting material (TLC) disappeared, i.e., after ˜30 min. Water was added to the mixture and the mixture was extracted with 5×200 ml ethylacetate. To remove the benzoic acid organic layer, the mixture was washed with sat. NaHCO3, followed by brine washing. The organic layer was then dried over Na2SO4, filtered, concentrated, and purified over a 330 g SiO2 column with hexane and hexane:ethylacetate (95:5) eluents. Appropriate fractions were collected to yield a white solid of 3,6-bis-triisopropylsilanyl-carbazole 5 10.0 g (54%).
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[C:7]1=[O:17])=O.[NH3:18]>>[C:3]([CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8](=[O:16])[C:7]1=[O:17])(=[O:2])[NH2:18]
Reactant: N
Reactant: COC(=O)Cn1c(=O)c(=O)[nH]c2ccccc21
Product: NC(=O)Cn1c(=O)c(=O)[nH]c2ccccc21
Reaction time: 18 h
Yield: 32 %

Procedure:
A mixture of 0.17 g (0.7 mmol) 1-methoxycarbonylmethylquinoxaline-2,3(1H,4H)-dione and 10 ml 25% aqueous ammonia was stirred for 18 h. The product was filtered off and washed with cold water to give 0.05 g (32%) 1-carbamoylmethylquinoxaline-2,3(1H,4H)-dione. M.p. >300° C. MS m/c: 219 (M+, 40%), 119 (100%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[Cl:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Clc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Clc1cccc(CC[C@H]2CNCCN2)c1
Temperature: 25 °C
Yield: 16.4 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (4.48 g, 11.07 mmol) in dichloroethane (40 ml). Cool the solution to 0° and then add 1-chloroethyl chloroformate (4.75 g, 33.21 mmol) dropwise. Warm the solution to ambient temperature and then heat it at reflux for 42 hours. Remove the dichloroethane under vacuum and reflux the resulting residue in methanol (100 ml) for 1 hour. Remove the methanol under vacuum and dissolve the resulting precipitate in 1N NaOH. Extract the aqueous layer with dichloromethane and then combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using dichloromethane/2N ammonia in methanol (90:10) to give 407.6 mg (16%) of the title compound: mp 93°–97°; mass spectrum (ion spray): m/z=225.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH2:61])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH:64]1([C:69](Cl)=[O:70])[CH2:68][CH2:67][CH2:66][CH2:65]1>>[CH3:1][O:2][C:3](=[O:63])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:41][CH:42]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:53]([C:56]1[S:60][C:59]([NH:61][C:69]([CH:64]2[CH2:68][CH2:67][CH2:66][CH2:65]2)=[O:70])=[N:58][C:57]=1[CH3:62])(=[O:55])=[O:54])=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(N)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1sc(NC(=O)C2CCCC2)nc1C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(S)-7-(2-amino-4-methyl-thiazole-5-sulfonyl)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (30 mg) was reacted with cyclopentanecarbonyl chloride according to General Procedure F to furnish (S)-3-(4′-cyano-biphenyl-4-yl)-2-({(S)-7-[2-(cyclopentanecarbonyl-amino)-4-methyl-thiazole-5-sulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester. This ester (25 mg), upon hydrolysis according to General Procedure B, gave the title compound (21 mg). LCMS (m/z): 1009.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[C:13]3[S:17]C(=S)N[C:14]3=[O:19])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:20].[Na+]>O>[C:1]1([C:7]2[CH:8]=[C:9]([CH2:12][C:13](=[S:17])[C:14]([OH:19])=[O:20])[S:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NC(=S)SC1=Cc1cc(-c2ccccc2)cs1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(=S)Cc1cc(-c2ccccc2)cs1
Temperature: 95 °C
Yield: 74 %

Procedure:
A suspension of product 5-((4-phenylthiophen-2-yl)methylene)-2-thioxothiazolidin-4-one (1.4 g, 4.6 mmol) in 12 mL of 10% aqueous NaOH was heated to 95° C. for 1 h. The solution was cooled to room temperature and diluted with water. The aqueous phase was washed with EtOAc, and acidified with 10% HCl. The precipitate that was formed was filtered, washed with water and dried under reduced pressure to get the product 3-(4-phenylthiophen-2-yl)-2-thioxopropanoic acid (0.9 g, yield 74%). MS (ESI) m/z: Calculated for C13H10O2S2: 262.01. found: 261.0 (M−H)−. The crude product was carried through without further purification
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1.Cl[C:17]1[C:18]2[C:25]([CH3:26])=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:23][C:19]=2[N:20]=[CH:21][N:22]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27]([O:29][CH3:30])=[O:28])[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[C:4]([O:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: Nc1ccc(F)cc1OC1CCOCC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
4-Fluoro-2-(tetrahydro-2H-pyran-4-yloxy)aniline (3.47 g, 16.4 mmol), methyl 4-chloro-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (3.99 g, 16.4 mmol) and para-toluene sulfonic acid (0.313 g, 1.64 mmol) were heated at reflux in anhydrous 1,4-dioxane (30 mL) for 1.5 hours. The solution was cooled to ambient temperature, the precipitate collected and washed with cold 1,4-dioxane to yield the title compound as yellow solid (6.17 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:27]N1CCCC1=O.[H-].[Na+].IC>O>[CH3:8][O:7][C:5](=[O:6])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:11]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:10]=1)([CH3:27])[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of dimethyl-(3-benzyloxy-4-nitrophenyl)malonate(2.3 g), N-methylpyrrolidinone(15 mL) and a 60% dispersion of sodium hydride in mineral oil(0.31 g) was stirred under an argon atmosphere at 0° C. for 0.5 h. The mixture was treated with iodomethane(0.8 mL) and stirred at ambient temperature for 4 h then treated with water (50 mL). The precipitate was collected and washed with water and hexane to give dimethyl-2-(3-benzyloxy-4-nitrophenyl)-2-methylmalonate(2.19 g). [m/e374(MH+)].
Reaction SMILES: COCCN(S(F)(F)F)CCOC.O[CH2:15][C@H:16]([NH:21][C:22]([C@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])=[O:23])[C:17]([O:19][CH3:20])=[O:18].BrC(Cl)(Cl)Cl.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[CH2:32]([O:31][C:29]([N:25]1[CH2:26][CH2:27][CH2:28][C@@H:24]1[C:22]1[O:23][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:21]=1)=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](CO)NC(=O)[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: COCCN(CCOC)S(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc([C@H]2CCCN2C(=O)OCc2ccccc2)n1
Reaction time: 0.5 h

Procedure:
Deoxo-flour (4.5 mL, 24.16 mmoles) was added drop-wise to a solution of (R)-benzyl 2-((S)-3-hydroxy-1-methoxy-1-oxopropan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (8.5 g, 22.0 mmoles) in CH2Cl2 (150 mL) at −20° C. The solution was stirred for 30 min and BrCCl3 (7.8 mL, 79.0 mmoles) was added drop-wise followed by DBU (11.8 mL, 79 mmoles). The reaction was stirred at 2-3° C., for 10 h., quenched with Satd. Aq. NaHCO3 solution and extracted with ethyl actetate. The organic layer was concentrated and chromatographed on silica gel (10% ethyl acetate/90% chloroform) to yield 6.95 of (R)-methyl 2-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)oxazole-4-carboxylate.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]3[CH:23]=[C:24]([N:28]4[CH2:32][CH2:31][NH:30][C:29]4=[O:33])[CH:25]=[CH:26][CH:27]=3)[CH2:16][CH2:15]2)[N:5]=1.[H-].[Na+].I[CH:37]([CH3:39])[CH3:38]>CN(C=O)C>[ClH:1].[ClH:1].[CH3:38][CH:37]([N:30]1[CH2:31][CH2:32][N:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][CH2:20][N:17]3[CH2:18][CH2:19][N:14]([C:10]4[CH:9]=[CH:8][CH:7]=[C:6]5[C:11]=4[CH:12]=[CH:13][C:4]([CH3:3])=[N:5]5)[CH2:15][CH2:16]3)[CH:23]=2)[C:29]1=[O:33])[CH3:39]
Reactant: CC(C)I
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N5CCNC5=O)c4)CC3)cccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(CCc4cccc(N5CCN(C(C)C)C5=O)c4)CC3)cccc2n1

Procedure:
The title compound was prepared according to the procedure described for Example 156 using 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (Example 85, 50 mg), DMF (1 mL), sodium hydride (60%, 10 mg) and 2-iodopropane (13 μL). Yield 17 mg.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:33](=[O:34])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([Cl:19])[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:37]I>CN(C)C=O.O.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:33](=[O:34])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=4)=[O:21])=[C:15]([Cl:19])[CH:16]([CH3:37])[S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CI
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS(=O)[C@H]12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC1C(Cl)=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Reaction time: 0.67 h

Procedure:
To a solution of p-nitrobenzyl 7-phenylacetamido-3-chloro-3-cephem-4-carboxylate-1-oxide (504 mg) in dimethylformamide (20 ml) one adds a 50% suspension of sodium hydride (48 mg) in mineral oil under nitrogen atmosphere, stirs for 40 minutes, adds methyl iodide (0.5 ml), stirs for 15 minutes at room temperature, dilutes with water, extracts with ethyl acetate, washes with water, dries, concentrates under reduced pressure, and purifies by chromatography to give p-nitrobenzyl 7-phenylacetamido-2-methyl-3-chloro-3-cephem-4-carboxylate-1-oxide (38 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.Cl[C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=1[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][C:2]1[N:6]=[CH:5][N:4]([C:8]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:9]=2[C:10]#[N:11])[N:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2C#N)n1
Temperature: 70 °C
Yield: 58 %

Procedure:
Step G (1): A mixture of 3-methyl-1H-1,2,4-triazole (6.83 g, 82 mmol), 2-chloro-5-nitrobenzonitrile (15 g, 82 mmol), and potassium carbonate (34.1 g, 246 mmol) in anhydrous acetonitrile (200 mL) was heated at 70° C. for 16 h. The dark brown reaction mixture was allowed to cool to rt and was poured into water (500 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using silica gel chromatography (40-100% ethyl acetate/hexane, linear gradient) to afford 2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrobenzonitrile (10.9 g, 58% yield). LC-MS (M+H)+=230.1. 1H NMR (500 MHz, chloroform-D) δ ppm 2.53 (s, 3 H) 8.10 (d, J=9.16 Hz, 1 H) 8.56 (dd, J=9.16, 2.44 Hz, 1 H) 8.68 (d, J=2.44 Hz, 1 H) 8.93 (s, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(N2CCNCC2)c2ccccc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCN(S(C)(=O)=O)CC2)c2ccccc2n1

Procedure:
2-Methyl-4-piperazin-1-yl-quinoline (227.3 mg, 1 mmol) was dissolved in anhydrous dichloromethane (7 ml), triethylamine was added (209 μl, 1.5 mmol), followed by methanesulfonyl chloride (85 μl, 1.1 mmol) which was added dropwise with ice-cooling. The mixture was diluted with dichloromethane and washed with 5% sodium bicarbonate solution. The wash solution was extracted with dichloromethane, the organic phases were combined and washed with 5% sodium bicarbonate solution, water and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure 265 mg of a white foam were obtained (0.87 mmol, 87%) which was used directly in the next step.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[CH:23]=O.O>CO>[OH:16][C:8]1[CH:7]=[CH:6][C:5]([C@@H:3]([OH:4])[C@@H:2]([NH:1][CH2:23][C:22]2[CH:25]=[C:26]([O:30][CH3:31])[C:27]([O:28][CH3:29])=[C:20]([O:19][CH3:18])[CH:21]=2)[CH3:17])=[CH:10][C:9]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Reactant: COc1cc(C=O)cc(OC)c1OC
Solvent: CO
Solvent: O
Product: COc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
To a solution of the amine (4) (111 mg, 0.43 mmol) and 3,4,5-trimethoxybenzaldehyde (111 mg, 0.55 mmol) in methanol (4 mL) was added borane-pyridine complex (135 μL, 1.28 mmol) at 40° C. and the resulting mixture was stirred for 1.5 hours. The reaction mixture was cooled to room temperature and water was added thereto, followed by extraction with a mixed solvent (ethyl acetate:methanol=10:1) and subsequent washing of the organic layer with saturated brine. The organic layer was dried and concentrated and the obtained crude product was purified by amine silica gel column chromatography (eluent; chloroform:methanol=7:1) to obtain the desired amine (8) as a white solid (67 mg, Yield: 36%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[Cl:18])=S.C(N)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:18][C:9]1[CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:7]=[C:5]1[NH:4][CH2:3][CH2:2][NH:1]1
Reactant: NCCNC(=S)Nc1c(Cl)cc([N+](=O)[O-])cc1Cl
Solvent: Cc1ccccc1
Solvent: NCc1ccccc1
Product: O=[N+]([O-])c1cc(Cl)c(N=C2NCCN2)c(Cl)c1

Procedure:
The thiourea (7) (0.36 g, 1.1 mmole) was suspended in 10 mL of toluene and excess benzylamine (1 mL) was then added. The mixture was heated at reflux for approximately 4 hours, and the solvent was then removed on a rotary evaporator. The residue was partitioned between 1M HCl and ethyl acetate. The aqueous phase was brought to pH 8-9 with 1N NaOH. The resulting yellow solid was collected by filtration, washed successively with water and hexane, and then air dried to provide 0.05 g (15%) of nitroclonidine.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:2][CH2:3][C:4]([OH:6])=[O:5].O[C:25]1[C:34]([F:35])=[C:32]([F:33])[C:30]([F:31])=[C:28]([F:29])[C:26]=1[F:27].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[NH:1]([C:7]([O:9][CH2:10][CH:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:8])[CH2:2][CH2:3][C:4]([O:6][C:25]1[C:26]([F:27])=[C:28]([F:29])[C:30]([F:31])=[C:32]([F:33])[C:34]=1[F:35])=[O:5]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CCNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(CCNC(=O)OCC1c2ccccc2-c2ccccc21)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of Fmoc-β-Ala-OH (311 mg, 1.0 mmol) and PfpOH(334 mg, 1.75 mmol) in DMF (2.5 mL) was added DCC (288 mg, 1.4 mmol) at 0° C. for 30 min and then room temperature for 15 h. The reaction mixture was filterd to remove DCUrea, the flitrate was evaporated in vacuo, and the residue was flush-chromatographed (CH2Cl2). The crude Fmoc-β-Ala-OPfp was recrystallized using hexane and CH2Cl2 to give the pure Fmoc-β-Ala-OPfp (429 mg 90%) as a white powder. To a solution of Fmoc-β-Ala-OPfp (100 mg, 0.21 mmol) and BocPNA-OH (41 mg, 0.19 mmol) in DMF (2 mL) was added diisoprppylethylamine (36 il, 0.21 mmol) and the reaction mixture was stirred at room temperature for 15 h. The reaction mixture was evaporated in vacuo and the residue was flush-chromatographed (0-10% MeOH/CH2Cl2) to give Fmoc-Gly-BocPNA-OH (41 mg, 42%). 1H NMR (DMSO-d6) δ 7.88 (d, J=7.4 Hz, 2H), 7.68 (d, J=7.4 Hz, 2H), 7.41 (t, J=7.3 Hz, 2H), 7.33 (t, J=7.3 Hz, 2H), 7.18 (m, 2H), 6.83 (brt) and 6.72 (brt) (2H), 4.3-4.2 (m, 4H), 4.05-3.9 (m, 3H), 3.33 (brt) and 3.29 (brt) (2H), 3.19 (m, 2H), 3.07 (brq) and 3.02 (brq) (2H), 1.36 (brs, 9H) ; 13C NMR (DMSO-d6) δ 171.20 (d), 170.85 (d), 155.93, 155.56, 143.87, 140.69, 127.55, 127.01, 125.09, 120.05, 77.73 (d), 65.30 (d), 59.69, 47.35 (d), 46.68, 46.49 (d), 37.99 (d), 36.72 (d), 28.14 (d).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[F:31])[C:25](O)=[O:26]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([F:31])=[C:22]([F:21])[CH:23]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1ccc(F)c(F)c1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(F)c(F)c1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 3,4-difluorobenzoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[S:18][C:17]3[C:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[N:15][C:14]([Sn](CCCC)(CCCC)CCCC)=[N:13][C:12]=3[CH:11]=2)[CH2:5][CH2:4]1.C1(S([N:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][C:55]=3[F:57])[C:50](Br)=[CH:49]2)(=O)=O)C=CC=CC=1.C1COCC1.[OH-].[Na+]>C(O)C.S1C=CC=C1C([O-])=O.[Cu+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:57][C:55]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:56]=1[NH:48][CH:49]=[C:50]2[C:14]1[N:15]=[C:16]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[C:17]2[S:18][C:10]([CH2:9][N:6]3[CH2:7][CH2:8][CH:3]([N:2]([CH3:38])[CH3:1])[CH2:4][CH2:5]3)=[CH:11][C:12]=2[N:13]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCC(N(C)C)CC3)cc2n1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2cccc(F)c21
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)C1CCN(Cc2cc3nc(-c4c[nH]c5c(F)cccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
To a mixture of dimethyl-[1-(4-morpholin-4-yl-2-tributylstannanyl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-amine (250 mg, 0.396 mmol), 1-benzenesulfonyl-3-bromo-7-fluoro-1H-indole (163 mg, 0.460 mmol), copper(I) thiophene-2-carboxylate (37 mg, 0.19 mmol), and Pd(PPh3)4 (44 mg, 0.038 mmol) was added THF (2 mL). The reaction vessel was evacuated and back filled with argon. The reaction mixture was diluted with hexane, filtered through a plug of solka floc, and the filtrate was concentrated. The residue was triturated with hexane and then purified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM). The elutant was then concentrated to give an off-white solid which was taken up in ethanol (2 mL). A 1 M aqueous NaOH solution (0.25 mL) was then added and the resulting mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated and triturated with water. The crude product was purified by flash chromatography (silica, 0-10% MeOH/NH4OH (9:1) in DCM) to give 118 as an off white solid (41.5 mg, 30%). LCMS: M+H+=495. 1H-NMR (300 MHz, DMSO-d6): δ 12.1 (s, 1H), 8.38 (d, 1H), 8.19 (d, 1H), 7.32 (s, 1H), 7.08 (m, 1H), 6.98 (m, 1H), 3.96 (m, 4H), 3.81 (m, 6H), 2.93 (d, 2H), 2.16 (s, 6H), 2.05 (t, 3H), 1.72 (d, 2H), 1.40 (m, 2H)