Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][C:31]([F:34])([F:33])[F:32])=[CH:26][C:25]=2[C:35]2[C:36]([N+:46]([O-])=O)=[N:37][N:38](C3CCCCO3)[CH:39]=2)=[CH:18][C:17]=1[F:49])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[Cl-:51].[NH4+]>[Fe].C(O)C>[ClH:22].[ClH:51].[NH2:46][C:36]1[C:35]([C:25]2[CH:26]=[C:27]([O:30][C:31]([F:32])([F:33])[F:34])[CH:28]=[CH:29][C:24]=2[O:23][C:19]2[C:20]([Cl:22])=[CH:21][C:16]([S:13]([NH:7][C:8]3[N:9]=[CH:10][S:11][CH:12]=3)(=[O:14])=[O:15])=[C:17]([F:49])[CH:18]=2)=[CH:39][NH:38][N:37]=1
Reactant: [Cl-]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2ccc(OC(F)(F)F)cc2-c2cn(C3CCCCO3)nc2[N+](=O)[O-])cc1F
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Product: Cl
Product: Nc1n[nH]cc1-c1cc(OC(F)(F)F)ccc1Oc1cc(F)c(S(=O)(=O)Nc2cscn2)cc1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
tert-Butyl[(5-chloro-2-fluoro-4-{2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]-4-(trifluoromethoxy)phenoxy}phenyl)sulfonyl]1,3-thiazol-4-ylcarbamate (Preparation 25, 3.70 g, 4.84 mmol), and saturated aqueous ammonium chloride solution (17 mL) were added to ethanol (62 mL). A white precipitate formed. Iron (0.541 g, 9.68 mmol) was added and the reaction mixture heated at 80° C. After 2 hours the reaction mixture was cooled, filtered and concentrated in vacuo. The residue was slurried in water and the solid collected by filtration. The solid was rinsed with water, then dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in a saturated solution of hydrogen chloride in methanol and heated at 50° C. for 2 hours. The solvent was removed in vacuo and the residue dissolved in a minimum amount of methanol. Ethyl acetate was added and the solution stirred for 4 hours while crystals formed. The solid was collected by filtration to afford the title compound as a white powder (1.75 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH2:7])=[C:5]([CH3:8])[S:4][C:3]=1[C:9]([O:11][CH3:12])=[O:10].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>CN(C)C=O.ClCCl>[CH3:8][C:5]1[S:4][C:3]([C:9]([O:11][CH3:12])=[O:10])=[C:2]2[C:6]=1[NH:7][C:14](=[O:16])[NH:1]2
Reactant: COC(=O)c1sc(C)c(N)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1sc(C)c2[nH]c(=O)[nH]c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 4777.4 %

Procedure:
Methyl 3,4-diamino-5-methylthiophene-2-carboxylate (3.0 g) was dissolved in a mixture of N,N-dimethyl formamide (5 ml) and dichloromethane (15 ml). To the solution was added triphosgene (2.4 g) in portions. The mixture was stirred for two days at room temperature, and precipitates were collected by filtration, washed with dichloromethane and dried. Resultant white powder (2.4 g) was suspended in N,N-dimethylformamide (25 ml). To the suspension was added sodium hydride (60% in oil; 0.55 g), and the mixture was stirred for three days at room temperature. The solvent was evaporated under reduced pressure. To the residue was added 2N-HC1. Resulting precipitates were collected by filtration, washed with water, ether and methanol successively, followed by drying to afford the title compound (82 g, 53%) as pale brown powder.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]1[C:20]2[C:15](=[C:16]([O:21]C)[N:17]=[CH:18][CH:19]=2)[N:14]([CH3:23])[CH:13]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31].C([O-])([O-])=O.[Cs+].[Cs+].Cl>CS(C)=O.O1CCOCC1>[F:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[F:31])[O:32][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:4][C:3]=1[C:12]1[C:20]2[CH:19]=[CH:18][NH:17][C:16](=[O:21])[C:15]=2[N:14]([CH3:23])[CH:13]=1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3F)cn(C)c12
Reactant: Oc1ccc(F)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(S(C)(=O)=O)ccc2Oc2ccc(F)c(F)c2)c2cc[nH]c(=O)c21
Yield: 38.8 %

Procedure:
A mixture of Example 17C (0.1 g, 0.299 mmol), 3,4-difluorophenol (0.058 g, 0.449 mmol) and Cs2CO3 (0.146 g, 0.449 mmol) in DMSO (5 mL) was stirred at 110° C. for 12 hours, cooled and partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous Na2SO4), filtered, and concentrated. The resulting residue (0.13 g, 0.405 mmol) and 4M HCl in dioxane (4 M, 13 mL) was heated at 70° C. for 12 hours, cooled and concentrated. The residue was purified by reverse phase HPLC (C18, CH3CN/water (0.1% TFA), 10-100%) to afford the title compound (0.05 g, 0.116 mmol, 38.7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (d, J=5.3 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.80 (dd, J=8.7, 2.4 Hz, 1H), 7.68 (s, 1H), 7.50 (dd, J=19.6, 9.2 Hz, 1H), 7.40 (ddd, J=11.5, 6.8, 2.9 Hz, 1H), 7.11 (d, J=8.6 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 6.95-6.88 (m, 1H), 6.54 (d, J=6.3 Hz, 1H), 4.11 (s, 3H), 3.26 (s, 3H). MS (ESI+) m/z 431.0 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:24]Br)=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)C>CN(C=O)C>[CH3:2][C:1]1[C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:13])[CH3:12])=[CH:6][C:5]=2[O:14][C:24]=1[C:22](=[O:23])[C:19]1[CH:20]=[CH:21][C:16]([CH3:15])=[CH:17][CH:18]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc2c(C)c(C(=O)c3ccc(C)cc3)oc2c1
Temperature: 60 °C

Procedure:
0.72 g (3.75 mmol) of N-(4-acetyl-3-hydroxy-phenyl)acetamide and 0.81 g (4.1 mmol) of 2-bromo-4-methylacetophenone were dissolved in 5 ml DMF and 1,55 g (11.25 mmol) of potassium carbonate were added. The suspension was heated to 60° C. for 1 h and ethylacetate was added. The organic phase was washed three times with water, one time with a NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was further purified by crystallisation (ethanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([OH:10])=O)[CH:3]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][NH2:38].CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:38][CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])=[O:10])[CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccn1
Reactant: CN(C)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCNC(=O)c1cc(Cl)ccn1
Temperature: 33 °C
Reaction time: 8 h
Yield: 108.4 %

Procedure:
4-Chloropicolinic acid (0.50 g, 3.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.67 g, 3.5 mmol) and 1-hydroxybenzotriazole hydrate (0.53 g, 3.5 mmol) were dissolved in DMF (6 mL). N1,N1-dimethylethane-1,2-diamine (0.381 mL, 3.49 mmol) and DIEA (0.62 mL, 3.5 mmol) were added, and the reaction was stirred at 33° C. overnight. The solution was cooled, diluted with water and extracted with methylene chloride. The organic layer was dried and concentrated to give the crude 4-chloro-N-(2-(dimethylamino)ethyl)picolinamide (0.79 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH3:33])[C:12]([N:15]2[CH2:32][CH2:31][C:18]3([C:22](=[O:23])[N:21]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([OH:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[CH2:17][CH2:16]2)=[N:13][CH:14]=1.CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.ClCCl.O1CCCC1>[OH:30][C@@H:27]1[CH2:26][CH2:25][C@H:24]([N:21]2[CH2:20][CH2:19][C:18]3([CH2:31][CH2:32][N:15]([C:12]4[C:11]([CH3:33])=[CH:10][C:9]([N:8]5[CH2:2][CH2:3][CH2:4][C:5]5=[O:6])=[CH:14][N:13]=4)[CH2:16][CH2:17]3)[C:22]2=[O:23])[CH2:29][CH2:28]1
Reactant: O=C(Cl)CCCBr
Reactant: Cc1cc(N)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(N2CCCC2=O)cnc1N1CCC2(CC1)CCN([C@H]1CC[C@@H](O)CC1)C2=O
Reaction time: 3 h

Procedure:
4-Bromobutanoyl chloride (13.0 μL) was added to a mixture of 8-(5-amino-3-methylpyridin-2-yl)-2-(cis-4-hydroxycyclohexyl)-2,8-diazaspiro[4.5]decan-1-one (18.0 mg) and 4-dimethylaminopyridine (14.5 mg) in dichloromethane (1.0 mL). The mixture was stirred for 3 h. Then potassium tert-butoxide in tetrahydrofuran (1.0 M, 0.20 mL) was added. The mixture was stirred for an additional hour. The solvent was evaporated. The residue was dissolved in methanol (1.8 mL), and purified by prep.-HPLC under basic condition to afford 2-(cis-4-hydroxycyclohexyl)-8-[3-methyl-5-(2-oxopyrrolidin-1-yl)pyridin-2-yl]-2,8-diazaspiro[4.5]decan-1-one. LCMS: (M+H)+=427.20.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].Cl.[CH2:30]([C:32]1[O:33][C:34]([CH2:37][N:38]2[C:43]3[CH:44]=[C:45]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[S:46][C:42]=3[C:41](=[O:53])[N:40]([CH:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[C:39]2=[O:60])=[CH:35][N:36]=1)[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([N:57]4[CH2:58][CH2:59][CH:54]([N:40]5[C:41](=[O:53])[C:42]6[S:46][C:45]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)=[CH:44][C:43]=6[N:38]([CH2:37][C:34]6[O:33][C:32]([CH2:30][CH3:31])=[N:36][CH:35]=6)[C:39]5=[O:60])[CH2:55][CH2:56]4)=[O:22])=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCc1ncc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)o1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5cnc(CC)o5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
The title compound is prepared analogously as described for example 1 using 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (167 mg; compound C10), 1-[(2-ethyl-1,3-oxazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (200 mg; compound B34), HBTU (175 mg), DIPEA (0.29 ml) and DCM (3 ml). Purification by flash column chromatography [amino phase silica gel, eluent: EtOAc/methanol, 97.5/2.5 (v/v)] and afterwards by preparative HPLC gives the title compound as a solid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[ClH:12].[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cccnc1
Solvent: Cc1ccccc1
Product: Cl
Product: O=C(Cl)c1cccnc1

Procedure:
1.5 g of nicotinic acid were heated to reflux in 1.8 ml of thionyl chloride for one and a half hours. After taking up in toluene and evaporating, the residue was triturated with ether, then dried to obtain 2.12 g of nicotinoyl chloride hydrochloride. 258 mg of the E isomer of Step B of Example 1 were dissolved in 1 ml of pyridine, and 93 mg (0.525 mM) of the freshly prepared nicotinoyl chloride hydrochloride were added and stirred for 2 hours under an inert atmosphere. After diluting with 10 ml of methylene chloride, washing with 1N hydrochloric acid and then with a solution of sodium bicarbonate, drying and evaporating, the residue was chromatographed over silica and eluted with a mixture of methylene chloride and acetone (9-1) to obtain 232 mg of 1,1-dimethylethyl (6S,7S) 7-[2-(2-trityl-aminothiazol-4-yl)-2-(Z)-(methoxyimino)-acetamido]-3-[(3-nicotinoyloxy)-1-(E)propenyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-2-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.CN(C=O)C.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH2:2][N:31]1[C:27](=[O:37])[C:28]3[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:30]1=[O:32])=[N:4]2
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 100 °C

Procedure:
To a heterogeneous mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluoro-phenyl)quinoxaline (0.1815 g, 0.4702 mmol) in DMF (3.444 mL, 0.4702 mmol) was added potassium phthalimide (0.2177 g, 1.175 mmol) and the heterogeneous mixture was stirred at 100° C. After stirring at 100° C. for 30 min, the mixture was concentrated under reduced pressure and triturated with water (30 mL). The precipitate was collected by filtartion. The resulting solid was filtered and washed with 2 N NaOH (30 mL) and then with water (100 mL), and air-dried to give 2-((5-chloro-3-(2-chloro-5-fluorophenyl)quinoxalin-2-yl)methyl)isoindoline-1,3-dione as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (1 H, dd, J=7.6, 1.4 Hz), 7.95-8.01 (1 H, m), 7.82-7.91 (5 H, m), 7.65-7.75 (2 H, m), 7.43-7.52 (1 H, m), 4.99 (2 H, br. s.); LC-MS (ESI) m/z 452.0 [M+H]+. The crude product was carried on crude without purification for the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=2)=[C:4](I)[CH:5]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:7]=1.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]#[CH:38]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]=[C:11]([Cl:13])[Cl:12])[CH:5]=[C:4]([C:38]#[C:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[Cl:30])[C:3]=1[O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][N:21]=1
Reactant: C#Cc1ccccc1Cl
Reactant: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2I)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2C#Cc2ccccc2Cl)nc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of protective gas, 0.1 g of 3-chloro-5-(3,3-dichloroprop-2-enyloxy)-1-iodo-2-[3-(5-trifluoromethylpyrid-2-yloxy)propyloxy]benzene, 0.03 g of 1-chloro-2-ethynylbenzene and 0.003 g of copper(I) iodide were dissolved in 1 ml of triethylamine. 0.005 g of bis(triphenylphosphine)palladium(II) chloride was added, and the mixture was stirred at 70° C. for 1 hour. The mixture was then allowed to cool and concentrated under reduced pressure, and the resulting residue was subjected to chromatographic purification. Yield: 0.085 g (84%)
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:4][CH:5]=[CH2:6])#[N:2].Br[CH2:14][C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[C:1]([C:3]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH2:4][CH:5]=[CH2:6])[CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:2]
Reactant: COC(=O)CBr
Reactant: C=CCC(C#N)c1ccccc1
Solvent: C1CCOC1
Product: C=CCC(C#N)(CC(=O)OC)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (−78° C.) of 4-cyano-4-phenyl-1-butene (6.23 g, 39.6 mmol) in anhydrous THF was added LIDS (1M in THF, 43.5 mL, 43.5 mmol) dropwise. The solution was stirred at −78° C. for 0.5 hour, then methyl bromoacetate (6.67 g, 43.6 mmol) was added dropwise. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using silica gel column chromatography eluting with 0-20% EtOAc in hexanes. The appropriate fractions were combined and concentrated to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (m, 5H), 5.57 (m, 1H), 5.14 (m, 2H), 3.49 (s, 3H), 3.49 (m, 2H), 2.78 (m, 2H) ppm. ES MS M+1=230.
Reaction SMILES: [NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31](OC)=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].O.[NH2:46][NH2:47]>C(O)C>[NH:1]([C:35]([O:37][CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:36])[C@H:2]([C:15]([NH:17][C@H:18]([C:31]([NH:46][NH2:47])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9]
Reactant: NN
Reactant: COC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)NN
Reaction time: 24 h

Procedure:
Compound XII (1.50 g, 2.4 mmoles) is dissolved in ethanol (10 ml) and hydrazine hydrate (1.16 ml, 24 mmoles) is added. The mixture is allowed to stand at room temperature for 24 hours and then evaporated in vacuo. The resulting solid residue is dissolved in water-saturated ethyl acetate and the solution is washed with water two times and quickly dried over magnesium sulfate. The crystalline precipitates which separated upon standing at room temperature are filtered off, washed with ether and dried in vacuo. Recrystallization from ethyl acetate-ether affords the hydrazide XIII in pure form; yield 1.41 g (94%), mp. 121°-123° C, [α]D22.5 - 8.5°±0.5° (c 1.0, dimethylformamide), -18.2°±0.6° (c 1.0, methanol).
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>O.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.CCO>[Cl:20][C:3]1[C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([F:21])[CH:27]=2)=[CH:7][N:6]=[C:5]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:4]=12
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(Br)cnc21
Reactant: OB(O)c1cccc(F)c1
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: CCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1ccc2c(Cl)c(-c3cccc(F)c3)cnc21
Temperature: 80 °C
Yield: 73.8 %

Procedure:
5-Bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.660 g, 1.78 mmol), 3-fluorophenylboronic acid (0.298 g, 2.13 mmol), Pd(PPh3)4 (0.103 g, 0.0888 mmol) and 10% K2CO3 (aq., 3.70 mL, 2.66 mmol) were added to an argon degassed solution of 2:1 toluene:EtOH (6 mL). The reaction was then heated to 80° C. for 18 hours. The reaction was then diluted with water and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified by column chromatography (1:1 hexanes:DCM) to give 4-chloro-5-(3-fluorophenyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (0.508 g, 73.9% yield).
Reaction SMILES: Br[CH:2]([CH2:15][CH:16]1[CH2:18][CH2:17]1)[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:4].[Na+].[I-].C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.O1CCCC1>[CH3:28][O:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][CH:2]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:3]([O:5][C@@H:6]([CH3:14])[C:7](=[O:13])[N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:4])=[CH:32][CH:31]=1
Reactant: C[C@H](OC(=O)C(Br)CC1CC1)C(=O)N1CCCC1
Reactant: COc1ccc(N)cc1
Agent: O=S([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(NC(CC2CC2)C(=O)O[C@@H](C)C(=O)N2CCCC2)cc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
To (1S)-1-methyl-2-oxo-2-tetrahydro-1-H-1-pyrrolylethyl 2-bromo-3-cyclopropylpropanoate (418 mg, 1.3 mmol), NaI (198 mg, 1.3 mmol), triethylamine (214 g, 2.1 mmol) and tetrahydrofuran (5 mL) were added. To the solution, p-methoxyaniline (211 mg, 1.7 mmol) and tetrahydrofuran (3 mL) were added. The mixture was stirred at room temperature for 24 hours and further at 40° C. for 20 hours. To the mixture, a saturated sodium sulfite aqueous solution and ethyl acetate were added for extraction. The obtained extract was dried with anhydrous magnesium sulfate, and the solvent was removed away under reduced pressure. The residue was purified with silica gel chromatography to obtain 270 mg of the target compound (yield: 57%, The diastereo ratio calculated by NMR analysis was 92:8.).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28](Cl)=[O:29])[CH2:22][CH2:21]2>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[Cl:27])[CH:23]([C:28]([N:8]1[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:29])[CH2:22][CH2:21]2
Reactant: O=C(Cl)C1CCc2cc(Cl)c(Cl)cc21
Reactant: CN1CCNC(CN2CCCC2)C1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)C2CCc3cc(Cl)c(Cl)cc32)C(CN2CCCC2)C1
Yield: 109.2 %

Procedure:
The procedure described in Example 24 was repeated, but using 1.67 g of 1-methyl-3-(pyrrolidin-1-ylmethyl)piperazine trihydrochloride, 3.6 ml of triethylamine and 1.5 g of 5,6-dichloroindan-1-carbonyl chloride, to afford 1.54 g of the title compound, melting at 245°-250° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][C:5]#[N:6].[CH2:8]1CCN2C(=NCCC2)C[CH2:9]1.[CH2:19](Br)[CH3:20]>C1COCC1>[CH3:1][O:2][C:3](=[O:7])[C:4]([C:5]#[N:6])([CH2:19][CH3:20])[CH2:8][CH3:9]
Reactant: COC(=O)CC#N
Reactant: CCBr
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCC(C#N)(CC)C(=O)OC
Temperature: 50 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
Methylcyanoacetate (Aldrich; 20 g, 0.201 mol) was dissolved in THF (250 mL), to this was added DBU (75 mL, 0.505 mol) and ethyl bromide (40 mL, 0.606 mol). The reaction was stirred at 50° C. for 2 hours before being cooled and quenched with sat NH4Cl(aq). The organic layer was separated and the remaining aqueous was extracted with diethyl ether (2×100 mL), dried and solvent removed in vacuo to yield yellow oil. Purification was achieved via distillation at 70° C. at 0.5 mbar to afford methyl2-cyano-2-ethyl-butanoate as a clear oil (20 g, 0.129 mol) which was reduced with hydrogen under pressure using Raney nickel catalyst (2 g). The reaction mixture was filtered and solvent evaporated to the title compound as a slightly dark oil. (16 g, 50%).