Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24]([N:26]([CH3:28])[CH3:27])[C:23]([F:29])=[CH:22][C:21]=1B(O)O>>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([C:21]2[CH:22]=[C:23]([F:29])[C:24]([N:26]([CH3:27])[CH3:28])=[CH:25][C:20]=2[Cl:19])[CH:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1cc(Cl)c(B(O)O)cc1F
Reactant: O=[N+]([O-])c1c(Cl)ccnc1OCc1ccccc1
Product: CN(C)c1cc(Cl)c(-c2ccnc(OCc3ccccc3)c2[N+](=O)[O-])cc1F
Yield: 58.9 %

Procedure:
2-Benzyloxy-4-chloro-3-nitro-pyridine (Wilde, et. al. WO 99/01454) (800 mg, 3.02 mmol) and 2-chloro-4-dimethylamino-5-fluorophenylboronic acid (Example B) (854 mg, 3.93 mmol) were treated substantially as described in Part A of Example 19a to give 715 mg (59%) of 2-benzyloxy-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridine: 1H NMR (400 MHz, CDCl3) δ ppm 8.27 (d, J=5.4 Hz, 1 H), 7.45–7.43 (m, 2H), 7.40–7.29 (m, 3H), 6.93 (d, J=5.4 Hz, 1 H), 6.89 (d, J=13.2 Hz, 1 H), 6.85 (d, J=8.0 Hz, 1 H), 5.53 (s, 2 H), 2.91 (d, J=1.2 Hz, 6 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[NH:8][N:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:11]=1)=[O:5])[CH3:2].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:20])[N:8]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]c1=O
Product: CCOC(=O)Cn1nc(-c2ccc(OC)cc2)cc(C(=O)OCC)c1=O
Yield: 84.5 %

Procedure:
Using 4-ethoxycarbonyl-6-(4-methoxyphenyl)-2H-pyridazin-3-one and ethyl bromoacetate as starting materials, the procedures of Example 1 were repeated likewise, whereby the title compound was obtained in a yield of 84.5%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][Mg]Cl>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]([OH:5])[CH3:11]
Reactant: C[Mg]Cl
Reactant: O=Cc1cc(F)ccc1Br
Solvent: C1CCOC1
Product: CC(O)c1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 75.3 %

Procedure:
To a solution of 2-bromo-5-fluoro-benzaldehyde (17.0 g, 83.7 mmol) in tetrahydrofuran (100 mL), cooled to 0° C. under nitrogen, was added methyl magnesium chloride solution (3M in tetrahydrofuran, 31.0 mL, 93.0 mmol, 1.1 eq.) dropwise over a 20 min period. The resulting solution was stirred at 0° C. for 45 min before quenching with aqueous ammonium chloride solution (1M, 17 mL). The resulting mixture was partitioned between pentane (300 mL) and water (100 mL). The organic phase was washed with brine (50 mL) and then dried over magnesium sulphate. This mixture was filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with a gradient of toluene in pentane (50:50 to 100:0 by volume) to produce the title compound as a colourless oil (13.8 g, 75%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[NH:14][C:15]([CH3:32])=[C:16]([C:28]([O:30][CH3:31])=[O:29])[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[N:18]=2)=[CH:7][CH:6]=1.[CH2:33](Br)[CH:34]=[CH2:35]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][S:12][C:13]2[N:18]([CH2:35][CH:34]=[CH2:33])[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=3)[C:16]([C:28]([O:30][CH3:31])=[O:29])=[C:15]([CH3:32])[N:14]=2)=[CH:7][CH:6]=1
Reactant: C=CCBr
Reactant: COC(=O)C1=C(C)NC(SCc2ccc(OC)cc2)=NC1c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCN1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A slurry of sodium hydride (168 mg, 4.2 mmole, 60% in mineral oil dispersion) in 5 ml of dry tetrahydrofuran at 0° C. under argon was treated dropwise with 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, methyl ester in 15 ml of dry tetrahydrofuran. After an additional 10 minutes at 0° C., allyl bromide was added and the reaction mixture was allowed to warm to room temperature overnight.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[C:6](=[C:18](OCC)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]1=[O:28])(=O)C.[C:29]([O:33][C:34]([N:36]([CH2:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1)[CH2:37][CH3:38])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]([CH2:39][C:40]1[CH:41]=[CH:42][C:43]([NH:44]/[C:18](=[C:6]2\[C:5](=[O:28])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=3)/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:45][CH:46]=1)[CH2:37][CH3:38])=[O:35])([CH3:30])([CH3:31])[CH3:32]
Reactant: CCOC(=O)c1ccc2c(c1)N(C(C)=O)C(=O)C2=C(OCC)c1ccccc1
Reactant: CCN(Cc1ccc(N)cc1)C(=O)OC(C)(C)C
Product: CCOC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(CN(CC)C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-ethoxycarbonyl-2-indolinone and 4-(N-tert.butoxycarbonyl-N-ethyl-aminomethyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C32H35N3O5
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12]Cl)([O-:3])=[O:2].[CH3:15][C@H:16]1[O:21][C@@H:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:14])[CH2:12][N:18]1[CH2:17][C@@H:16]([CH3:15])[O:21][C@@H:20]([CH3:22])[CH2:19]1)([O-:3])=[O:2]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=C(CCl)Nc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: C[C@@H]1CN(CC(=O)Nc2ccccc2[N+](=O)[O-])C[C@H](C)O1
Yield: 72.3 %

Procedure:
A mixture of N-(2-nitrophenyl)-2-chloroacetamide (8.6 g), 2,6-cis-dimethylmorpholine (9.2 g) and ethanol (100 ml) was heated together under reflux for 3 hours. The ethanol was evaporated off and the residue treated with water (100 ml). The resultant suspension was filtered and the solid recrystallised from ethanol to give N-(2-nitrophenyl)-2-(2,6-cis-dimethylmorpholino)acetamide (8.5 g), m.p. 127°-129° C. (with decomposition) which was then dissolved in methanol (100 ml). Platinum oxide (0.3 g) was added to the solution which was then shaken in an atmosphere of hydrogen at atmospheric pressure and laboratory temperature until 1.9 litres of hydrogen had been absorbed. The mixture was filtered and the ethanol evaporated off to give a white solid which was recrystallised from water to give N-(2-aminophenyl)-2-(2,6-cis-dimethylmorpholino)acetamide (5.4 g), m.p. 104°-106° C. (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23](=S)[CH2:24][C:25]([CH:27]1[CH2:29][CH2:28]1)=O)=[O:4].Cl.[CH:32]1([NH:36][NH2:37])[CH2:35][CH2:34][CH2:33]1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:21])([F:22])[F:20])(=[O:11])=[O:12])[CH2:7][N:6]1[C:23]1[N:36]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:37]=[C:25]([CH:27]2[CH2:29][CH2:28]2)[CH:24]=1)=[O:4]
Reactant: NNC1CCC1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=S)CC(=O)C1CC1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1C1CCC1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-1-(3-cyclopropyl-3-oxo-thiopropionyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with cyclobutylhydrazine hydrochloride (CAS Reg. No. 158001-21-9) to give the title compound as yellow foam.
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:11]([O-])=[CH:12][C:13](=O)[C:14]([O:16]CC)=[O:15])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([NH:50][NH2:51])[CH:45]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:11]2[N:50]([C:46]3[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=3)[N:51]=[C:13]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC)c1
Reactant: NNc1cccnc1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: COc1cc(Br)cc(-c2cc(C(=O)O)nn2-c2cccnc2)c1

Procedure:
500 mg (1.19 mmol) of the compound of Example 6A is reacted analogously to the synthesis of the compound of Example 20A with 260 mg (1.79 mmol) of 3-pyridylhydrazine hydrochloride. After hydrolysis, 240 mg (54% of theory) of the title compound is obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57](O)=[O:58])(=[O:46])=[O:45])[CH:38]=[CH:37]2.[N:60]1([CH2:66][C:67]2[CH:68]=[C:69]3[C:74](=[CH:75][CH:76]=2)[CH2:73][CH:72]([NH2:77])[CH2:71][CH2:70]3)[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]1>C(Cl)Cl>[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39]([S:44]([N:47]1[CH2:52][CH2:51][N:50]3[CH:53]=[CH:54][CH:55]=[C:49]3[CH:48]1[CH2:56][C:57]([NH:77][CH:72]1[CH2:71][CH2:70][C:69]3[C:74](=[CH:75][CH:76]=[C:67]([CH2:66][N:60]4[CH2:65][CH2:64][CH2:63][CH2:62][CH2:61]4)[CH:68]=3)[CH2:73]1)=[O:58])(=[O:45])=[O:46])[CH:38]=[CH:37]2
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Reactant: NC1CCc2cc(CN3CCCCC3)ccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)NC3CCc4cc(CN5CCCCC5)ccc4C3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
DIPEA (2.5 eq.), HOAt (1.0 eq.) and EDCl (1.5 eq.) were added to a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-1-yl)acetic acid S2 (0.2325 mmol, 1.0 eq.) in DCM (3 ml) at 0° C. and the mixture was stirred for 15 min at RT. Then 6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine A5 (0.2325 mmol, 1.0 eq.) in DCM (2 ml) was added at 0° C. and the mixture was stirred overnight at RT. The reaction mixture was diluted with DCM and extracted with aqueous NaHCO3 solution, aqueous NH4Cl solution, water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), concentrated to small volume and purified by column chromatography (alox). Yield: 58%; m/z=627.4 [MH]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].Br[CH:19]([CH3:21])[CH3:20]>CN(C)C=O>[CH3:20][CH:19]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH3:21]
Reactant: CC(C)Br
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1OC(C)C
Temperature: 60 °C

Procedure:
2-methyl-5-nitroaniline (40 g) was dissolved in refluxing 10% sulphuric acid (600 ml), cooled to 0° C. whereupon the salt separates out. With continuous stirring, sodium nitrite solid (18 g) was added in small portions. The diazitization was complete when a positive starch/KI test was observed. This diazonium solution was added at once to a vigorously refluxing solution of water (800 ml) and concentrated sulphuric acid (400 ml). Refluxing was continued until all gassing had ceased. A solid had precipitated out and, upon cooling to ambient temperature, was collected and dried to give crude 2-methyl-5-nitrophenol. This crude phenol (36.8 g) in dimethylformamide (200 ml) along with anhydrous K2CO3 (35 g) and 2-bromopropane (50 ml) was stirred and warmed to 60° C. for 12 hours. After cooling, the solvent was removed, the residue treated with water and the product extracted with ether. This ether solution was washed with 2N KOH, water, dried (MgSO4) and evaporated to give 1-(1-methylethoxy)-2-methyl-5-nitrobenzene, bp. 80°-85° C./0.15 mm., 34.5 g. This nitrobenzene (34.5 g) in methanol (250 ml) was reduced on a parr hydrogenator using Raney nickel. After removal of the catalyst and solvent, the product, 3-(1-methylethoxy)-4-methyl-benzenamine, bp. 80°-85° C./0.05 mm., 25 g. was obtained. This amine (10 g) in methylene chloride (50 ml) and crushed ice (50 g) was stirred whilst thiophosgene (6.5 ml) in methylene chloride (25 ml) was added dropwise. The reaction was stirred overnight at ambient temperature. After separating the organic layer, the methylene chloride solution was washed with water, dried and evaporated to leave a pale yellow oil, bp. 80°-85° C./0.04 mm of 5-isothiocyanato-1-(methylethoxy)-2-methylbenzene, 12,4 g. Ethyl 3-amino-4,4,4-trifluoro-2-butenoate (11 g) was added portionwise to a stirred suspension of sodium hydride (2.5 g, 60%) in tetrahydrofuran (50 ml) at 15° C. When complete, the reaction was chilled to -70° C. (acetone/ dry ice), whereupon the above isothiocyanate (12.4 g.) in THF (25 ml) was added at once. The temperature rose to -50° C. before cooling to -70° C. After stirring to ambient temperature and leaving overnight a solid had precipitated out. The solvent was removed, water added, washed with ether and acidified. A pale yellow solid had precipitated out. This was collected on a filter, washed with water, dried and recrystallized from IPA to give 2,3 dihydro-3-[3-(1-methylethoxy)-4-methylphenyl]- 2-thioxo-6-(trifluoromethyl)-4(1H)-pyrimidinone, mp. 227°-228°.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.CS(O[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])(=O)=O>>[CH3:25][O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: COc1ccccc1COS(C)(=O)=O
Reactant: O=Cc1cccc2[nH]ccc12
Product: COc1ccccc1Cn1ccc2c(C=O)cccc21

Procedure:
The same procedures used in Example 1 were repeated except for using 725 mg of indole-4-carbaldehyde and 2-methoxybenzyl methanesulfonate instead of the benzyl bromide used in Example 1 to give 906 mg of 1-(2-methoxybenzyl)indole-4-carbaldehyde as a yellow oily substance. The yield thereof was found to be 68%.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([C:21]1[CH:22]=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[N:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH3:34][Si:35]([CH3:51])([CH2:45][CH2:46][Si:47]([CH3:50])([CH3:49])[CH3:48])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:51][Si:35]([CH3:34])([CH2:45][CH2:46][Si:47]([CH3:48])([CH3:49])[CH3:50])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[CH:22][C:21]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][N:25]=2)=[CH:28][CH:29]=1
Reactant: CCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: C[Si](C)(C)CC[Si](C)(C)CCCCCCCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCc1cnc(-c2ccc(OCCCCCCCC[Si](C)(C)CC[Si](C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethylazodicarboxylate (0.065 g, 0.375 mmol) in THF (5.0 ml) was added dropwise to a stirred solution of 4-(5-octylpyrimidin-2-yl)-phenol (0.085g, 0.300 mmol), compound 17 (0.083 g, 0.300 mmol) and triphenylphosphine (0.098 g, 0.375 mmol) in THF (10 ml). The treaction mixture was stirred at room temperature for 24 h, the solvent removed in vacuo and the residues purified by column chromatography [silica gel eluted with hexane/ethyl acetate (9:1)] to yield a colorless solid that was recrystallized from acetonitrile.
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.CCN(CC)CC.CN([C:23]([O:27][N:28]1N=NC2C=CC=N[C:29]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CNOC>C(Cl)Cl.CN(C=O)C>[CH3:23][O:27][N:28]([CH3:29])[C:10]([C:2]1[S:1][C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=1)=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2cnccc2s1
Agent: CNOC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of thieno[3,2-c]pyridine-2-carboxylic acid (D′-1) (11.5 g, 64.2 mmol) in DCM (200 mL) and DMF (50 mL) was added Et3N (19.5 g, 26.6 mL, 192.6 mmol) followed by HATU (36.6 g, 96.3 mmol). The reaction solution was stirred at room temperature for 20 mins, and then treated with N,O-dimethylhydroxylamine hydrochloride (6.9 g, 70.6 mmol). Stirring continued overnight at room temperature. The solvent was removed. The residue was dissolved in EtOAc and washed with water and brine. The organic layer was dried and concentrated. The residue was purified by chromatography on silica gel to give the title compound. MS (m/z): 223 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[H-].[Na+].[O:10]([C:17]1[CH:36]=[CH:35][C:20]([O:21][CH2:22][CH2:23]C2C=C(S([O-])(=O)=O)C=CC=2C)=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C=O>[O:10]([C:17]1[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:3]2[C:2]([Cl:1])=[C:6]([Cl:7])[N:5]=[CH:4]2)=[CH:35][CH:36]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1nc[nH]c1Cl
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1CCOc1ccc(Oc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncn(CCOc2ccc(Oc3ccccc3)cc2)c1Cl
Temperature: 60 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A mixture of 8.43 g of 4,5-dichloroimidazole, 80 ml of dimethylformamide and 1.83 g of sodium hydride is heated, with stirring, for 3 hours at 60° C. Subsequently, a solution of 23.04 g of 2-[(p-phenoxyphenoxy)-ethyl]p-toluenesulfonate in 40 ml of dimethylformamide is dripped in. The mixture is heated for 12 hours at 100° C., cooled, poured into 50 ml of ice water, and extracted several times with ethyl acetate, and the combined extracts are washed first with 5% strength aqueous sodium hydroxide solution and then with water. Drying over sodium sulfate, removal of the solvent under reduced pressure and recrystallization from methyl tert-butyl ether gives 16.9 g (81%) of N-[(p-phenoxyphenoxy)-ethyl]-4,5-dichloroimidazole; m.p.: 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=O)=[CH:4][CH:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]C#N)=[CH:14][CH:13]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2=[N:8][O:10][C:18]([C:15]3[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=3)=[C:6]2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2onc3ccc(Br)cc23)cc1

Procedure:
13 g 1-bromo-4-nitrobenzene, 7.68 mL 2-(4-fluorophenyl)acetonitrile and 3.9 g sodium hydroxide were stirred in 130 mL ethanol at 40° C. for 24 hours. After the reaction solution was left and cooled, water was added thereto and the reaction solution was extracted with ethylacetate. The organic solvent was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) and then recrystallized from hexane/ethyl acetate to give 2.9 g of the title compound as pale brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][O:32]C3CCCCO3)[CH:26]=2)[CH:20]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:30]=[CH:29][N:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[CH:20]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(Cl)c(Cl)cc2N1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (177 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M and subsequent treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (220 mg, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[CH:6]=[CH:5][C:3]=1[NH2:4].[NH:10]1[CH:14]=[N:13][CH:12]=[N:11]1>CN(C=O)C.C(OCC)(=O)C.[Cu](I)I>[Cl:1][C:2]1[CH:8]=[C:7]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[CH:6]=[CH:5][C:3]=1[NH2:4]
Reactant: Nc1ccc(I)cc1Cl
Reactant: c1nc[nH]n1
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(-n2cncn2)cc1Cl
Temperature: 25 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
2-Chloro-4-iodoaniline (2 g, 7.9 mmol), 1,2,4-triazole (0.62 g, 9 mmol) and copper iodide (0.15 g, 0.79 mmol) in DMF (10 ml) were heated to 140° C. and stirred under dry nitrogen for 72 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (50 ml). The organic layer was washed with water, brine, dried over sodium sulfate and filtered. The solvent was removed under vacuum and the residue purified by silica gel column chromatography eluting with 20% ethyl acetate in dichloromethane to give the title compound as a white powder (1.2 g, 78%). 1H-NMR (500 MHz, CDCl3): δ 4.43 (s, 2H), 6.76 (d, J=8.7 Hz, 1H), 7.23 (dd, J=2.5 Hz, 8.6 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.94 (s, 1H), 8.36 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:2]1.[H-].[Na+].I[CH3:23]>C1COCC1>[CH3:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[CH:2]1
Reactant: CI
Reactant: CC(C)(C)OC(=O)NCCc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(CCNC(=O)OC(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
To a solution of tert-butyl (2-(1H-Indol-3-yl)ethyl)carbamate (1.50 g, 5.77 mmol) in anhydrous THF (15 mL) was added sodium hydride (300 mg, 7.50 mmol, 60% in mineral oil) at 0° C. under nitrogen. After the resulting reaction mixture was stirred at room temperature for 15 min, iodomethane (982 mg, 6.92 mmol) in THF (5 mL) was added slowly at 0° C. The resulting mixture was stirred at room temperature for 3 h and quenched with saturated aqueous ammonium chloride solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The organic solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (0.6% MeOH in DCM) to afford the title compound (1.29 g, 4.71 mmol, 81% yield) as a brown solid. MS (ESI) m/z 275.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:15][C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][NH:15][C:16]4[O:17][C:18]([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=5)=[N:19][N:20]=4)=[CH:6][CH:7]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CNc1nnc(-c2ccccc2)o1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNc4nnc(-c5ccccc5)o4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylmethyl]-(5-phenyl-[1,3,4]oxadiazol-2-yl)-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.