Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:30][C@@H:31]1[CH2:35][N:34]([C:36](=[O:56])[C@@H:37]([NH:42][C:43](=[O:55])[C@@H:44]([N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])[C@H:33]([C:57](=[O:69])[NH:58][C@H:59]2[C:68]3[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=3)[CH2:62][CH2:61][CH2:60]2)[CH2:32]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:39][C:38]([CH3:40])([CH3:41])[C@H:37]([NH:42][C:43](=[O:55])[C@@H:44]([N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])[CH3:45])[C:36](=[O:56])[N:34]1[CH2:35][C@@H:31]([NH:30][C:1](=[O:4])[C:2]#[CH:3])[CH2:32][C@H:33]1[C:57](=[O:69])[NH:58][C@H:59]1[C:68]2[C:63](=[CH:64][CH:65]=[CH:66][CH:67]=2)[CH2:62][CH2:61][CH2:60]1
Reactant: C#CC(=O)O
Reactant: C[C@@H](C(=O)N[C@H](C(=O)N1C[C@@H](N)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)N[C@H]1C[C@@H](C(=O)N[C@@H]2CCCc3ccccc32)N(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.2 %

Procedure:
To a solution of propiolic acid (0.06 mL, 0.90 mmol) in DMF (2 mL) at 0° C. was added HATU (123 mg, 0.32 mmol) followed by tert-butyl ((S)-1-(((S)-1-((2S,4S)-4-amino-2-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)pyrrolidin-1-yl)-3,3-dimethyl-1-oxobutan-2-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (100 mg, 0.18 mmol) and DIEA (0.06 mL, 0.36 mmol). The reaction mixture was stirred at rt for 1 h and diluted with ethyl acetate and brine. The organic layer was separated, washed with aq. NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 90% EtOAc/hexane) to afford the title compound as a white solid (76 mg, 70%). 1H NMR (CDCl3) δ 8.60 (d, J=6.6 Hz, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.25 (m, 1H), 7.16-6.98 (m, 3H), 5.23-5.08 (m, 1H), 4.73 (d, J=8.8 Hz, 1H), 4.63-4.48 (m, 1H), 4.32 (d, J=8.6 Hz, 1H), 3.96 (dd, J=10.9, 5.0 Hz, 1H), 3.75 (d, J=11.0 Hz, 1H), 2.80-2.70 (m, 5H), 2.43 (d, J=13.9 Hz, 1H), 2.18 (ddd, J=14.0, 8.9, 6.4 Hz, 1H), 2.06-1.94 (m, 1H), 1.91-1.80 (m, 4H), 1.46 (s, 10H), 1.30-1.25 (m, 3H), 0.76 (s, 9H); MS(ESI+) m/z 610.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21]([O:10][CH2:9][CH2:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: OCCc1cccc(Cl)n1
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3cccc(Cl)n3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
To a solution of 2-6-chloro-2-pyridinyl)ethanol (Example 470, 250 mg, 1.59 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 698 mg, 3.17 mmol) in THF (4 mL) were added PPh3 (832 mg, 3.17 mmol) and DIAD (641 mg, 3.17 mmol). The reaction mixture was vigorously stirred at rt for 24 h, concentrated under reduced pressure, and the residue was purified by silica gel chromatography (6:1 hexanes/EtOAc) to give the product (170 mg, 30%). 1H NMR (400 MHz, CDCl3) δ 1.28 (t, 3H), 1.72-1.77 (m, 1H), 2.34-2.43 (m, 2H), 2.71 (dd, 1H), 2.81-2.89 (m, 2H), 3.21 (t, 2H), 3.51-3.52 (m, 1H), 4.17 (q, 2H), 4.31 (t, 2H), 6.69 (d, 1H), 6.76 (s, 1H), 7.04 (d, 1H), 7.19 (dd, 2H), 7.57 (t, 1H).
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH2:22].[N:28]1([C:34]2[N:35]=[C:36]([CH2:41][C:42]([O-])=[O:43])[NH:37][C:38](=[O:40])[CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.[Na+]>CN(C)C=O>[F:19][C:20]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:21]=1[NH:22][C:42](=[O:43])[CH2:41][C:36]1[NH:37][C:38](=[O:40])[CH:39]=[C:34]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[N:35]=1
Reactant: Nc1ccc(F)cc1F
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.8 %

Procedure:
2.5 ml of pyridine, 233 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 400 mg of 2,4-difluoroaniline are added to a solution of 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of Example 1 in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 16 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinced with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 205 mg of N-(2,4-difluorophenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a pinkish solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:20])[CH:18]=3)[NH:13][C:12]2=[O:21])[N:4]=1.CN1C=CN=C1.[F:28][CH:29]([F:34])[S:30](Cl)(=[O:32])=[O:31].O>ClCCl>[F:28][CH:29]([F:34])[S:30]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:21])(=[O:32])=[O:31]
Reactant: O=S(=O)(Cl)C(F)F
Reactant: COc1nc(OC)nc(C2C(=O)Nc3ccc(F)cc32)n1
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1nc(OC)nc(C2C(=O)N(S(=O)(=O)C(F)F)c3ccc(F)cc32)n1
Temperature: -10 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-fluoro-1,3-dihydro-2H-indol-2-one (50 g) and 1-methyl-1H-imidazole (30.5 g) are introduced as initial charge in 430 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, a solution of difluoromethanesulfonyl chloride (41.8 g) in 70 ml of dichloromethane is added dropwise at −15° C. to −5° C. over the course of 30 minutes, and the mixture is after-stirred for 4 hours at −15° C. to 0° C. 1-Methyl-1H-imidazole (2.7 g) and difluoromethanesulfonyl chloride (4.9 g) are added to the reaction mixture and stirred for 2 hours at 0° C. With ice cooling, 300 ml of water are added to the reaction mixture, the mixture is after-stirred for 30 minutes and the organic solvent is largely distilled off in vacuo. The residue is filtered, the solid product is washed twice with 150 ml of water and twice with 40 ml of acetonitrile and dried. This gives the title compound as a solid in an HPLC purity of 96% (63.9 g, 95% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)[S:5][C:6]=1[CH:7]=O.[NH2:15][C:16]1[C:21]([NH2:22])=[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])[C:19]([Br:34])=[CH:18][N:17]=1.C([O-])(=O)C.[NH4+]>>[Br:34][C:19]1[C:20]([NH:23][C@@H:24]2[C@@H:29]3[CH2:30][C@@H:26]([CH:27]=[CH:28]3)[C@@H:25]2[C:31]([NH2:33])=[O:32])=[C:21]2[N:22]=[C:7]([C:6]3[S:5][C:4]([N:9]4[CH2:13][CH2:12][C@@H:11]([OH:14])[CH2:10]4)=[N:3][C:2]=3[Cl:1])[NH:15][C:16]2=[N:17][CH:18]=1
Reactant: O=Cc1sc(N2CCC(O)C2)nc1Cl
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4sc(N5CC[C@@H](O)C5)nc4Cl)nc23)[C@H]2C=C[C@@H]1C2
Yield: 4 %

Procedure:
In a similar fashion to Compound LXXXVII, 4-Chloro-2-(3-hydroxy-pyrrolidin-1-yl)-thiazole-5-carbaldehyde (180.77 mg, 0.77687 mmol), (1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (210.19 mg, 0.62149 mmol), and Ammonium acetate (95.813 mg, 1.2430 mmol) were reacted to produce 13.82 mg (4%) of the title compound. (300 MHz, DMSO-d6) 12.68 (s, 1H), 8.01 (s, 1H), 7.73 (s, 1H), 7.23 (s, 1H), 7.14 (s, 1H), 6.38-6.31 (m, 2H), 5.15 (s, 1H), 5.05 (t, J=17 Hz, 8.5 Hz, 1H), 4.44 (s, 1H), 3.54 (m, 3H), 2.87 (s, 1H), 2.73 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.21 (d, J=8 Hz, 1H), 2.10 (m, 1H), 1.96 (m, 1H), 1.38 (d, J=8 Hz, 1H). MS=553 (M+H), HPLC: 2.07 min. (G Method)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH:21]=[CH2:22])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH2:21][CH3:22])[CH3:2]
Reactant: C=Cc1cc(OCc2ccccc2)ccc1OCC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1ccc(O)cc1CC
Yield: 78.1 %

Procedure:
A solution of (4-benzyloxy-2-vinylphenoxy)acetic acid ethyl ester (0.55 g, 1.77 mmol) in ethanol (15 mL) was treated with 5% Pd/C (70 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan oil (0.31 g, 77%): 1H NMR (400 MHz, CDCl3) δ 6.68 (d, J=2.9 Hz, 1H), 6.62 (d, J=8.8 Hz, 1H), 6.57 (dd, J=8.8, 2.9 Hz, 1H), 4.62 (s, 1H), 4.57 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 3.73 (q, J=7.0 Hz, 2H), 2.66 (q, J=7.7 Hz, 2H), 1.34-0.92 (m, 6H); MS (FIA) m/e 225 (M+1).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].CCCCCCC>C1(C)C=CC=CC=1>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]4[CH:22]=[CH:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[N:12]=3)[CH:10]=2)=[N:49][C:48]=1[CH3:53])(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: Cc1nc(Cl)sc1S(=O)(=O)NC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)n2)cn1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cn(-c3cc(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)n3)cn2)sc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (Example G.11) (0.718 g, 1.0 mmol), 2-chloro-4-methyl-thiazole-5-sulfonic acid tert-butylamide (Example H.5) (0.295 g, 1.1 mmol), tetrakis(triphenyl-phosphine)palladium (0.058 g, 0.044 mmol) in toluene (5 mL) was heated under reflux conditions for 18 h. Cooled to rt, some precipitate occurred, diluted with toluene (˜5 mL), added heptane, filtered the precipitate off, washed with toluene/heptane, dried in HV to give the title compound as a white solid (384 mg, 59%). MS (ISP) 590.4 [(M+H)+]; mp>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=[O:11])=[C:5]([C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[CH:4]=1.O.[NH2:25][NH2:26].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[CH2:9][C:10](=[O:11])[NH:25][N:26]=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)[C:5]=2[CH:4]=1
Reactant: NN
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccc([N+](=O)[O-])cc2)c1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(c1ccc([N+](=O)[O-])cc1)=NNC(=O)C2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
7.8 g of 2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid is mixed in 200 ml of tetrahydrofuran with 2.3 ml of 80% hydrazine hydrate and stirred for 6 hours at room temperature. After standing overnight, it is mixed with 50 ml of water, and the tetrahydrofuran is drawn off in a rotary evaporator. The precipitated 2-(4-methoxy-2-(4-nitrobenzoyl)phenyl)acetic acid hydrazide (4.9 g) is suctioned off and stirred in 37 ml of glacial acetic acid at room temperature for 2 hours. It is diluted with 37 ml of water and suctioned off. 4.37 g of 8-methoxy-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepin-4-one with a melting point of 282° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39]([C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](O)=[O:45])=[O:40].C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[OH:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][NH:38][C:39](=[O:40])[C:41]1[CH:49]=[CH:48][CH:47]=[C:43]([C:44]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]3)=[CH:4][C:3]=2[C:14]2[CH:15]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[N:17]=[CH:18][N:19]=2)=[O:45])[CH:42]=1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Reactant: O=C(O)c1cccc(C(=O)NCCOCCO)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCOCCO)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (300 mg, 0.70 mmol, 1.00 equiv) in N,N-dimethylformamide (6 mL). This was followed by the addition of 3-(2-(2-hydroxyethoxy)ethylcarbamoyl)benzoic acid (302.2 mg, 1.19 mmol, 1.70 equiv) at room temperature. To this was added triethylamine (156 mg, 1.54 mmol, 2.20 equiv). To the mixture was added EDC.HCl (148.2 mg, 0.78 mmol, 1.10 equiv) at room temperature, followed by HOBT (104.4 mg, 0.77 mmol, 1.10 equiv) at room temperature. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 83.6 mg (15%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.76 (s, 1H), 8.40 (s, 1H), 8.039 (t, J=8.1 Hz, 2H), 7.74 (s, 1H), 7.63˜7.57 (m, 3H), 7.53˜7.50 (m, 2H), 7.47˜7.40 (m, 2H), 6.93 (s, 1H), 4.81 (s, 2H), 3.71˜3.58 (m, 8H), 3.43˜3.39 (m, 4H), 1.84˜1.81 (m, 6H). MS (ES, m/z): 663 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:6][CH:7]=[C:8]([Br:10])[CH:9]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:17]([NH:20][CH2:21][CH:22]=[CH2:23])[CH:18]=[CH2:19].O>C(#N)C>[Br:10][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[CH2:2][N:20]([CH2:21][CH:22]=[CH2:23])[CH2:17][CH:18]=[CH2:19])[S:6][CH:7]=1
Reactant: C=CCNCC=C
Reactant: O=C(CBr)c1cc(Br)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: C=CCN(CC=C)CC(=O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 1-(4-bromothiophen-2-yl)ethanone (10 g, 48.8 mmol) in methanol (98 mL) and dichloromethane (163 mL) is added tetra-n-butylammonium tribromide (28.8 g, 58.5 mmol). The reaction mixture is concentrated under reduced pressure at 50° C. to give a residue which is purified by silica gel chromatography, eluting with dichloromethane to give crude 2-bromo-1-(4-bromo-2-thienyl)ethanone. To a solution of the crude 2-bromo-1-(4-bromo-2-thienyl)ethanone in acetonitrile (200 ml) is added potassium carbonate (20.2 g, 146 mmol) and diallylamine (9.48 g, 97.5 mmol). The reaction is stirred at room temperature for 2 hours. Water is added and the solution is extracted with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude title compound. ES/MS (m/e): (79Br/81Br) 300/302 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.[CH2:34]([N:36](CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:29])[NH:36][CH3:34])=[CH:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(NCc3ccc(C(=O)O)cc3)c2CC1
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Yield: 75.1 %

Procedure:
Combine 3-(tert-butoxycarbonyl)-6-(4-carboxy-benzylamino)-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.1 g, 0.3 mmol), methylamine hydrochloride (31 mg, 0.46 mmol), triethylamine (0.1 g, 0.9 mmol), HATU (0.2 g, 0.5 mmol), anhydrous DMF (3 mL) and stir at ambient temperature for 17 h. Partition the reaction mixture between brine (5 mL) and diethyl ether (5 mL), separate the organic layer and dry over anhydrous Na2SO4. Evaporate the solvent to obtain 3-(tert-butoxycarbonyl)-7-chloro-6-(4-methylcarbamoyl-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (0.1 g, 93%). MS (ES+) m/z: 344 (M+H-Boc)+.
Reaction SMILES: [CH:1](=[C:3](/[C:11]1[C:15](B2OC(C)(C)C(C)(C)O2)=[CH:14][N:13]([CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[N:12]=1)\[CH:4]=[CH:5]/[C:6]([N+:8]([O-:10])=[O:9])=[CH2:7])\C.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]2[N:43]([S:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)(=[O:58])=[O:57])[C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52][N:53]([CH3:55])[CH3:54])=[CH:48][CH:47]=3)=[CH:45][C:38]=12>>[CH3:55][N:53]([CH2:52][C:49]1[CH:48]=[CH:47][C:46]([C:44]2[N:43]([S:56]([C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)(=[O:58])=[O:57])[C:39]3=[N:40][CH:41]=[CH:42][C:37]([C:15]4[C:11]([C:3]5[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][CH:1]=5)=[N:12][N:13]([CH2:25][CH2:26][N:27]([CH3:35])[C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH:14]=4)=[C:38]3[CH:45]=2)=[CH:51][CH:50]=1)[CH3:54]
Reactant: CN(C)Cc1ccc(-c2cc3c(Br)ccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: C=C(/C=C\C(=C/C)c1nn(CCN(C)C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1)[N+](=O)[O-]
Product: CN(C)Cc1ccc(-c2cc3c(-c4cn(CCN(C)C(=O)OC(C)(C)C)nc4-c4ccc([N+](=O)[O-])cc4)ccnc3n2S(=O)(=O)c2ccccc2)cc1

Procedure:
Following the procedure described for Intermediate 100 using 1,1-dimethylethyl {2-[3-[(1E,2Z)-1-ethylidene-4-nitro-2,4-pentadien-1-yl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}methylcarbamate and ({4-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]phenyl}methyl)dimethylamine provided the title compound. ESMS [M+H]+: 736.4.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13]1.N1CCCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:17]/[C:14]3[CH:15]=[CH:16][S:12][CH:13]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccsc1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Solvent: C1CCNCC1
Solvent: CO
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccsc1
Yield: 77.1 %

Procedure:
In a manner similar to the method described in Example 1, 6-chlorooxindole (2 g, 11.9 mmol) (Alfa) was reacted with 3-thiophenecarboxaldehyde (1.09 mL, 11.9 mmol) (Aldrich) and piperidine (1.18 mL, 11.9 mmol) in methanol to give E/Z-6-chloro-3-thiophen-3-ylmethylene-1,3-dihydro-indol-2-one as a yellow solid (Yield 2.4 g, 77%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:12])[CH:11]=1)[C:5](=O)[CH2:6][Br:7].Cl.[NH2:14][OH:15].O>CO>[Br:7][CH2:6][C:5]([C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=1)=[N:14][OH:15]
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: ON=C(CBr)c1cc(F)cc(F)c1

Procedure:
34.5 g (146.8 mmol) 3,5-difluorophenacylbromide, 30.6 g (440.4 mmol) hydroxylamine-hydrochloride, 44.0 ml of water and 320.0 mL methanol were stirred overnight at RT. The reaction mixture was concentrated by rotary evaporation using the rotary evaporator and mixed with 150 mL water and extracted twice with ethyl acetate. The combined organic phases were washed with water, dried and evaporated to dryness by rotary evaporation.
Reaction SMILES: [OH-].[Na+].O.[Cl:4][C:5]1[S:6][C:7]([Cl:12])=[CH:8][C:9]=1[CH:10]=O.[CH3:13][C:14]([CH3:16])=[O:15]>>[Cl:4][C:5]1[S:6][C:7]([Cl:12])=[CH:8][C:9]=1[CH:10]=[CH:13][C:14](=[O:15])[CH3:16]
Reactant: CC(C)=O
Reactant: O=Cc1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1cc(Cl)sc1Cl
Reaction time: 1 h

Procedure:
To a solution of 2,5-dichlorothiophene (100.0 g) and dichloromethylmethylether (165.3 g) in dichloromethane (800 ml) was added dropwise a solution of titanium tetrachloride (272.7 g) in dichloromethane (160 ml) at −10 to −15° C. taking 50 minutes, and at the same temperature, the mixture was stirred for 30 minutes. The reaction solution was poured into ice, and the organic layer was washed with water, sodium hydrogen carbonate solution, water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 2,5-dichloro-3-formylthiophene (115.0 g) as oil. To a mixture of acetone (1000 ml), sodium hydroxide (28.6 g) and water (1200 ml) was added at 0° C. a solution of 2,5-dichloro-3-formylthiophene (58.6 g) in acetone (200 ml) for 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. Under reduced pressure, acetone was evaporated, and the crystals were filtered, washed with water and dried to give 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g). To a solution of 20% sodium ethoxide in ethanol (211 g) was added diethyl malonate (99.3 g) at room temperature, and then 4-(2,5-dichlorothiophen-3-yl)-3-buten-2-one (136.6 g) little by little. The mixture was stirred at room temperature for 30 minutes, heated for 2 hours while stirring, and cooled. The solvent was evaporated, and to the residue was added water. The aqueous layer was washed with ethyl acetate and concentrated, to which was added 2M sodium hydroxide (340 ml). The mixture was stirred at 100° C. for 2 hours and cooled. To the mixture was added 2.5M sulfuric acid (340 ml) for 15 minutes, and the mixture was stirred at 100° C. for 1.5 hours. The mixture was cooled, and precipitated crystals were filtered and washed with ethyl acetate-isopropylether (1:4) and isopropylether to give 5-(2,5-dichlorothiophen-3-yl)cyclohexane-1,3-dione (78.9 g) as colorless crystals.