Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1>C(O)C>[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]2[C:22]([C:13]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([S:1]([OH:11])(=[O:10])=[O:2])=[CH:8][CH:7]=3)=[N:14][CH:15]=[N:16]2)=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ncnc2c1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2ncnc3cc(C(F)(F)F)ccc23)cc1

Procedure:
0.8 grams of sulphanilic acid and an equimolar quantity of 4-chloro-7-trifluoromethylquinazoline were heated in 20 ml of 50% aqueous ethanol at 100° C. for 2 hours. The suspension was cooled and the solid was filtered off, washed with water and dried to give 1.03 g of the title compound. The sulphonyl chloride hydrochloride derivative for use in part (b) below was prepared in similar manner to Examples 1 and 2.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.C(=O)([O-])O.[Na+:35]>O>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:35]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1

Procedure:
In a solution of 0.2 g sodium hydrogen carbonate in 4 ml of water was dissolved 0.619 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride. The solution was subjected to column chromatography on dextran gel (Sephadex LH-20, Pharmacia), development being carried out with water. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.42 g of the captioned compound.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH2:12])=[CH:4][CH:3]=1.CN(C)C.Cl[S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19]>ClCCl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][NH:12][S:18]([CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(=[O:20])=[O:19])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CCOCCN)s1
Reactant: COC(=O)CCS(=O)(=O)Cl
Agent: CN(C)C
Solvent: ClCCl
Product: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of step c) as the hydrochloride salt (1.50 g) was stirred under nitrogen in dichloromethane (25 ml). Trimethylamine (2.21 ml) was added followed by methyl 3-(chlorosulphonyl)propanoate (1.18 g). The mixture was stirred at room temperature overnight. The solution was diluted with a further amount of dichloromethane and the organics washed with dilute hydrochloric acid then water, then dried (MgSO4). The mixture was filtered and the volatiles removed in vacuo to give the subtitle compound as an oil (1.4 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]>C(Cl)Cl>[CH2:7]([N:5]1[CH2:6][C@@H:2]([NH:1][S:38]([C:35]2[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=2)(=[O:39])=[O:40])[C@H:3]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[CH2:4]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1N
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (3R,4R)-4-amino-1-benzylpyrrolidin-3-ylcarbamate (5.8 g, 20 mmol) in 100 mL of CH2Cl2, triethylamine (4.04 g, 40 mmol) was added following by addition of 4-nitrobenzenesulfonyl chloride (1.1 eq) and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1-2% MeOH in CHCl3 to give the title product.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.N#N.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C([O-])(=O)C=C.Cl>C(OC)(C)(C)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)CS
Reactant: C=CC(=O)OC
Agent: C=CC(=O)[O-]
Agent: Cl
Agent: N#N
Solvent: COC(C)(C)C
Solvent: C1CCNCC1
Product: COC(=O)CCSCC(=O)OC
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052 mol) were charged to an inerted jacketed reactor equipped with an addition funnel, mechanical stirrer, N2 line and thermocouple thermometer. Methyl acrylate (250 g, 2.87 mol) was then added slowly over a period of 30 min keeping the temperature at approximately 45° C. Upon complete addition, the mixture was stirred at 45° C. for 30 min Piperidine (17.9 g, 210 mmol) was added and stirring at 45° C. continued for 30 min (in order to scavenge of excess acrylate). Tert-butylmethylether (MTBE) (251 ml) was charged, the mixture was cooled to 15° C. and 1 M HCl (251 ml) was added. The mixture was stirred for 5 min and the organic layer was collected and washed with water (251 ml). The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50° C. Dichloromethane (251 ml) was charged and the mixture was again concentrated under reduced pressure by distillation at 40-45° C. Crude product III (480 g) was used in the next step without further purification.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:34][C:33]=1[F:44])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[CH2:45]([N:47]([CH2:51][CH3:52])[C:48](Cl)=[O:49])[CH3:46]>>[CH2:45]([N:47]([CH2:51][CH3:52])[C:48]([N:41]1[CH2:42][CH2:43][N:38]([C:35]2[CH:36]=[CH:37][C:32]([O:31][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:33]([F:44])[CH:34]=2)[CH2:39][CH2:40]1)=[O:49])[CH3:46]
Reactant: CCN(CC)C(=O)Cl
Reactant: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: CCN(CC)C(=O)N1CCN(c2ccc(OCc3ccccc3)c(F)c2)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)-piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(4-benzyloxy-3-fluorophenyl)piperazine (286 mg) and diethylcarbamoyl chloride (139 μL), respectively, to provide crude N,N-diethyl-4-(4-benzyloxy-3-fluorophenyl)-1-piperazinecarboxamide (370 mg).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:27]([O:31][C:32](=[O:54])[N:33]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]=[O:52])=[C:47]([F:53])[N:46]=1)[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:39][CH:40]=1)([CH3:30])([CH3:29])[CH3:28].[Cl-].[NH4+]>O1CCCC1>[C:27]([O:31][C:32](=[O:54])[N:33]([C:45]1[CH:50]=[CH:49][C:48]([CH:51]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:52])=[C:47]([F:53])[N:46]=1)[CH2:34][C:35]1[CH:36]=[N:37][C:38]([C:41]([F:43])([F:42])[F:44])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)nc1)c1ccc(C=O)c(F)n1
Reactant: COc1cnc2c(c1)c(I)cn2S(=O)(=O)c1ccccc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cnc2c(c1)c(C(O)c1ccc(N(Cc3ccc(C(F)(F)F)nc3)C(=O)OC(C)(C)C)nc1F)cn2S(=O)(=O)c1ccccc1
Temperature: -25 °C
Yield: 58.2 %

Procedure:
To 1-benzenesulfonyl-3-iodo-5-methoxy-1H-pyrrolo[2,3-b]pyridine (575, 0.326 g, 0.000788 mol) in tetrahydrofuran (3.00 mL) at −45° C. under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.380 mL) was added slowly. The reaction was allowed to warm to −25° C. in 30 minutes, and then cooled to −45° C. followed by adding (6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (565, 80.0 mg, 0.20 mmol, prepared as described in Example 60, Scheme 176) in tetrahydrofuran (1.0 mL). The reaction was allowed to warm to room temperature over 2 hours. The reaction was poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (576, 0.080 g, 60%). MS (ESI) [M+H+]+=688.1.
Reaction SMILES: C(O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C.[C:51]([O:55][C@@H:56]([C:61]1[C:90]([CH3:91])=[C:89]([CH:92]=[O:93])[C:88]2=[N:94][C:85]3=[CH:86][N:87]2[C:62]=1[N:63]1[CH2:100][CH2:99][C:66]([CH3:101])([O:67][CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]([CH3:98])[O:73][C:74]2[CH:75]=[CH:76][C:77]([F:97])=[C:78](F)[C:79]=2[C:80]2[CH:95]=[C:84]3[CH:83]=[CH:82][CH:81]=2)[CH2:65][CH2:64]1)[C:57]([O:59][CH3:60])=[O:58])([CH3:54])([CH3:53])[CH3:52]>>[C:51]([O:55][C@@H:56]([C:61]1[C:90]([CH3:91])=[C:89]([CH:92]=[O:93])[C:88]2=[N:94][C:85]3=[CH:86][N:87]2[C:62]=1[N:63]1[CH2:64][CH2:65][C:66]([CH3:101])([O:67][CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]([CH3:98])[O:73][C:74]2[CH:75]=[CH:76][C:77]([F:97])=[CH:78][C:79]=2[C:80]2[CH:95]=[C:84]3[CH:83]=[CH:82][CH:81]=2)[CH2:99][CH2:100]1)[C:57]([O:59][CH3:60])=[O:58])([CH3:54])([CH3:52])[CH3:53]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 82 %

Procedure:
Prepared in 82.0% yield from Methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for Methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 686.4.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>>[CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:7][CH:8]=1
Reactant: CSc1ccc(CC(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1ccc(SC)cc1
Temperature: 100 °C
Reaction time: 26 h

Procedure:
A mixture of 4-(methylthio)phenylacetic acid (5.10 g, 28.0 mmol) and H2SO4 (0.155 mL, 2.80 mmol) in EtOH (150 mL) in a 500 mL round bottom flask, were stirred at 100° C. for 26 hours. The reaction was concentrated in vacuo, diluted with EtOAc (200 mL), washed with deionized water (2×150 mL), and then with brine (100 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo. The crude product was purified by flash column chromatography (silica, 0-20% EtOAc in hexane) to give the title compound (5.95 g). MS m/e=211 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([CH:13]([OH:15])[CH3:14])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:16]1[N:20]=[CH:19][N:18]([C:21](N2C=NC=C2)=[O:22])[CH:17]=1>C(#N)C>[N:18]1([C:21]([O:15][CH:13]([C:10]2[CH:11]=[N:12][C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][CH:9]=2)[CH3:14])=[O:22])[CH:17]=[CH:16][N:20]=[CH:19]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(O)c1ccc(-c2ccccc2)nc1
Solvent: CC#N
Product: CC(OC(=O)n1ccnc1)c1ccc(-c2ccccc2)nc1

Procedure:
Synthesized using compound 45a (170 mg, 0.85 mmol), CDI (692 mg, 4.27 mmol) and acetonitrile (10 mL) according to Method E. Crude product was purified by flash chromatography on silica-gel using a mixture of hexane/ethyl acetate (2:1) as eluent. White solid. Yield: 107 mg, 43%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=1.82 (d, J=6.9 Hz, 3H), 6.16 (q, J=6.6 Hz, 1H), 7.08 (dd, J=1.7, 0.8 Hz, 1H), 7.41-7.53 (m, 4H), 7.76-7.85 (m, 2H), 7.98-8.03 (m, 2H), 8.17 (d, J=1.3 Hz, 1H), 8.78 (d, J=1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=21.5, 74.9, 117.1, 120.4, 126.9, 128.8, 129.3, 130.8, 133.3, 134.7, 137.0, 138.6, 147.9, 148.0, 158.0; MS (ESI): m/z=294.28 [M+H]+.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]([OH:13])=O)[CH2:4][CH2:3][CH2:2]1.[NH2:14][CH2:15][CH2:16][CH2:17][C@H:18]1[O:22][C:21](=[O:23])[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19]1>>[O:23]=[C:21]1[N:20]([C:24]2[CH:25]=[CH:26][C:27]3[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=3[CH:34]=2)[CH2:19][C@@H:18]([CH2:17][CH2:16][CH2:15][NH:14][C:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[NH:1][CH2:2][CH2:3][CH2:4]3)=[O:13])[O:22]1
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: O=C(O)c1cccc2c1NCCC2
Product: O=C1CSc2ccc(N3C[C@@H](CCCNC(=O)c4cccc5c4NCCC5)OC3=O)cc2N1
Yield: 85 %

Procedure:
Starting from 1,2,3,4-tetrahydroquinoline-8-carboxylic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (114 mg; 85% yield).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:35](Cl)(=[O:37])[CH3:36]>ClCCl>[C:35]([NH:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N)CC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(C)=O)CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-(cis-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (150 mg, 0.364 mmol) was suspended in dichloromethane (2 ml) under nitrogen at room temperature and triethylamine (153 μl, 1.09 mmol) was added followed by acetyl chloride (29 μl, 0.4 mmol). The reaction was stirred at room temperature for 1.5 h and the mixture was quenched with sat. sodium bicarbonate solution (3 ml). The organic phase was separated and the aqueous phase was washed with dichloromethane (2×5 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:concentrated aqueous ammonia (95:5:0.5, by volume) and the product was triturated with diethylether (2×3 ml) to give N-(cis-4-Acetylamino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (50 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(COC)OC.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>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.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1cc(Cl)ccc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Cl)ccc1-c1ccccc1
Yield: 90.7 %

Procedure:
A degassed mixture of ethyl 5-chloro-2-iodobenzoate (0.621 g, 2.00 mmol), Pd(PPh3)4 (0.116 mg, 0.1 mmol), dimethoxyethane (20 mL), phenylboronic acid (0.268 g, 2.2 mmol), K2CO3 (0.829 g, 6.0 mmol), and water (5 mL) was heated under reflux for 6 h. Solvent was removed under reduced pressure. The residue was diluted with sat. NH4Cl (15 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by chromatography to afford ethyl 5-chloro-2-phenylbenzoate (0.473 g, 91%) as colorless oil. MS (ESI) m/z: 261.0 (M+H+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]#[N:7])[CH2:2][CH3:3].[NH2:8][OH:9]>C(Cl)Cl>[OH:9]/[N:8]=[C:6](\[NH2:7])/[CH2:5][O:4][CH2:1][CH2:2][CH3:3]
Reactant: CCCOCC#N
Reactant: NO
Solvent: ClCCl
Product: CCCOC/C(N)=N/O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of propoxyacetonitrile (3.03 g) and hydroxylamine (2.01 g, 50 wt % in water) is stirred for 2 h at 100° C. At RT DCM is added, the organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as an oil.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22]CC)=[O:21].S([O-])(O)(=O)=O.[K+]>CCCCCC.CS(C)=O>[C:20]([CH2:19][N:8]1[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=2[CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[CH:17][C:9]1=2)([OH:22])=[O:21]
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: CCOC(=O)CBr
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Product: O=C(O)CN1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60% sodium hydride (3.60 g, 90 mmol) was washed with hexane under argon atmosphere, and then suspended in dimethyl sulfoxide (130 ml). 5,11-Dihydrodibenzo[b,e][1,4]oxazepine (14.8 g, 75.0 mmol) was added to the obtained suspension. They were stirred at room temperature for 60 minutes. A solution of ethyl bromoacetate (16.7 g, 150 mmol) in dimethyl sulfoxide (30 ml) was added dropwise in the obtained solution, and they were stirred at room temperature for 70 minutes and then at 50° C. for 2 hours. The reaction liquid was poured into 5% aqueous potassium hydrogensulfate solution. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous sodium chloride solution. After drying, the solvent was evaporated under reduced pressure. The obtained residue was dissolved in 200 ml of methanol. 200 ml of 4 M aqueous sodium hydroxide solution was added to the obtained solution, and they were stirred at room temperature for 1 hour. After the extraction with ethyl acetate, 40 ml of 6 M hydrochloric acid was added to the aqueous layer to adjust pH to 1. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and then with saturated aqueous sodium chloride solution. After drying, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography. The product was eluted with ethyl acetate and hexane (5:1) and then with ethyl acetate and hexane (1:3). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-(carboxymethyl)dibenzo[b,e][1,4] oxazepine in the form of a light yellow solid (6.40 g, 33.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Br[CH2:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O.[OH-].[NH4+]>C(O)C>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[N:1]=[C:2]3[N:6]([CH:8]=2)[CH:5]=[CH:4][S:3]3)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(C(=O)CBr)c1
Reactant: Nc1nccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc(-c2cn3ccsc3n2)c1
Reaction time: 18 h
Yield: 82.9 %

Procedure:
To a mixture of 2-aminothiazole (2.7 g, 0.0267 mol) and 2-bromo-3′-methoxyacetophenone (6.0 g, 0.0262 mol) is added absolute ethanol (100 ml). The reaction is allowed to reflux with vigorous stirring for 18 hours (checked by HPLC). The reaction mixture is reduced to half its original volume in vacuo. The remaining liquid is poured onto ice and the solution made basic by the addition of ammonium hydroxide solution (30%). The resulting fine solid is filtered and washed with water resulting in a dark yellow solid product. The solid product is dried in a vacuum oven at 50° C. to provide 6-(3-methoxyphenyl)-imidazo[2,1-b]thiazole (5.0 g, 81%). 400 MHz 1H NMR (DMSO-d6) δ 8.18 (s, 1H), 7.88 (d, J=4.4 Hz, 1H), 7.36-7.42 (m, 2H), 7.28 (t, J=8.1 Hz, 1H), 7.22 (d, J=4.4 Hz, 1H), 6.82 (ddd, J=8.1, 2.6, 1.1 Hz, 1H), 3.80 (s, 3H). LCMS: 231 [M+H].
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][N:29]([CH3:37])[CH2:30][CH2:31][CH2:32][S:33](Cl)(=[O:35])=[O:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:10]=[C:11]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:33]([CH2:32][CH2:31][CH2:30][N:29]([CH3:37])[CH3:28])(=[O:35])=[O:34])[CH2:22][CH2:21]2)[C:12]2[N:13]([C:15]([CH3:18])=[N:16][N:17]=2)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nnc2c(NC3CCNCC3)cc(N(C)Cc3ccccc3)nn12
Reactant: CN(C)CCCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nnc2c(NC3CCN(S(=O)(=O)CCCN(C)C)CC3)cc(N(C)Cc3ccccc3)nn12
Temperature: 50 °C
Reaction time: 16 h

Procedure:
N6-Benzyl-3,N6-dimethyl-N8-piperidin-4-yl-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (0.05 g; 0.11 mmol; purity 80%) was slurred up in 0.3 ml DMA. 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for 16 hours. Another portion of 3-Dimethylamino-propane-1-sulfonyl chloride Hydrochlorid (0.03 g; 0.14 mmol) and DIPEA (0.06 ml; 0.34 mmol) were added and stirred at 50° C. for additional 16 hours. The crude material was purified by using reversed phase chromatography under acid conditions.