Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li]CCCC.[CH:34](=O)/[CH:35]=[CH:36]/[CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH3:42]>>[CH2:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH:34]/[CH:35]=[CH:36]/[CH2:37][CH2:38]/[CH:39]=[CH:40]\[CH2:41][CH3:42]
Reactant: CC/C=C\CC/C=C/C=O
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Product: CC/C=C\CC/C=C/C=CCc1ccccc1
Yield: 60.9 %

Procedure:
Starting from phenethyltriphenylphosphonium bromide (3.05 g, 6.82 mmol, 1.0 equiv.), n-BuLi (1.6M in hexanes, 4.3 mL, 6.82 mmol, 1.0 equiv.) and (2E,6Z)-nona-2,6-dienal (1.41 g, 10.2 mmol, 1.5 equiv.), 0.94 g (61%) of the title compound as a colorless oil was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 995:5).
Reaction SMILES: [CH:1]#[CH:2].[Cl:3][SiH:4]([CH2:6][SiH:7]([Cl:9])[Cl:8])[Cl:5]>C1C=CC=CC=1>[Cl:3][Si:4]1([Cl:5])[CH:2]=[CH:1][Si:7]([Cl:9])([Cl:8])[CH2:6]1
Reactant: C#C
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Solvent: c1ccccc1
Product: Cl[Si]1(Cl)C=C[Si](Cl)(Cl)C1

Procedure:
Hydrosilation of acetylene with bis(dichlorosilyl)methane in the presence of Pt((CH2 =CHSiMe2)2O)2. Into the same apparatus as described in Example 1 were placed 18 μl of Pt((CH2 =CHSiMe2)2O)2 in 1,1,3,3-tetramethyl-1,3-divinyl-1,3-disiloxane (4 weight percent Pt) and 20 ml of dried benzene. Acetylene gas was blown into the flask at 90 ml/min for 5 hours. The products were vacuum distilled at 0.5 torr to yield a mixture comprising 3.32 g of 1,1,3,3-tetrachloro-1,3-disilacyclopent-4-ene (TCD-GC) area 6.2%); 1,1,3,3-tetrachloro-1,3-disilacyclopentane (TCD-GC area 47.9%); and 1,1,3,3,6,6,8,8-octachloro-1,3,6,8-tetrasilaoctane (TCD-GC area 27.1 %).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].Cl[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(Oc2cc(Cl)ccc2Cl)c([N+](=O)[O-])c1
Yield: 81.8 %

Procedure:
2,5-Dichlorophenol (17.86 g, 109.54 mmol) and 4-chloro-3-nitrobenzonitrile (10.00 g, 54.77 mmol) were combined with K2CO3 (37.85 g, 273.85 mmol) in THF (300 mL). The reaction mixture was refluxed for 48 hrs and then the solid was filtered over a bed of Celite. After rinsing the residue with copious amounts of DCM, the filtrate was concentrated to produce a yellow solid. The solid was triturated with minimal DCM and collected via vacuum filtration to yield compound 34 (13.84 g, 81.7% yield, 100.0% pure). 1H NMR (500 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.12 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.73 (d, J=9 Hz, 1H), 7.65 (d, J=2 Hz, 1H), 7.48 (dd, J1=9 Hz, J2=2 Hz, 1H), 7.21 (d, J=9 Hz, 1H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][N:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH:10]=O>>[CH2:1]([NH:3][CH2:10][C:6]1[N:5]([CH3:4])[CH:9]=[CH:8][CH:7]=1)[CH3:2]
Reactant: Cn1cccc1C=O
Reactant: CCN
Product: CCNCc1cccn1C

Procedure:
prepared by reaction of ethylamine with 1-methyl-1H-pyrrole-2-carbaldehyde
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:10][CH2:11][CH3:12])([C:6](Br)([F:8])[F:7])=[O:5].I[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.CCOCC>CN(C=O)C.Cl[Cu]>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([C:6]([P:4](=[O:5])([O:10][CH2:11][CH3:12])[O:3][CH2:2][CH3:1])([F:8])[F:7])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: CCOP(=O)(OCC)C(F)(F)Br
Reactant: O=[N+]([O-])c1ccc(I)cc1
Agent: Cl[Cu]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C(F)(F)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Under N2, a mixture of bromodifluoromethyl diethylphosphonate (0.427 g, 1.6 mmol) and Cd powder (180 mg, 1.6 mmol) in DMF (0.5 mL) was stirred at room temperature for 2 h. Most of Cd disappeared. 4-Iodo-1-nitrobenzene (249 mg, 1.00 mmol) and CuCl (115 mg, 1.16 mmol) were then added. The mixture was again stirred at room temperature for 3 h. Ether (20 mL) was added to the reaction mixture and the precipitated solids were filtered off and washed with 10 mL of ether. The combined ether layers were washed with NH4Cl (aq), dried over MgSO4, and evaporated to give the title product (267 mg, yield: 86%). 1H NMR (CD3OD, 400 MHz): δ=1.33 (t, J=7.2 Hz, 6 H), 4.20-4.28 (m, 4 H), 7.86 (d, J=8.4 Hz, 2 H), 8.39 (d, J=8.4 Hz, 2 H). MS (ES+): m/z 310.06 [MH+]. HPLC: tR=3.92 min (ZQ3, polar—5 min).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].C12(CO)CC3CC(CC(C3)C1)C2.[F:47][C:48]([F:57])([F:56])[CH:49]1[CH2:54][CH2:53][CH:52]([OH:55])[CH2:51][CH2:50]1>>[Cl:17][C:18]1[C:19]([O:55][C@H:52]2[CH2:53][CH2:54][C@@H:49]([C:48]([F:47])([F:56])[F:57])[CH2:50][CH2:51]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OC1CCC(C(F)(F)F)CC1
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC12CC3CC(CC(C3)C1)C2
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(O[C@H]2CC[C@@H](C(F)(F)F)CC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with 4-(trifluoromethyl)cyclohexanol, the title compound was obtained as a colorless solid (0.02 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.35 (d, J=12.5 Hz, 1H), 4.94 (s, 1H), 2.87 (s, 6H), 2.46-2.35 (m, 1H), 2.03-1.93 (m, 2H), 1.72-1.53 (m, 6H); MS (ES−) m/z 445.2, 447.2 (M−1).
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[C:9]([C:11]2[CH:33]=[CH:32][C:14]3[N:15]([CH3:31])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:42]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[O:43])=[CH:22][C:21]=4[O:29][CH3:30])=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1OC)n2C)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCO
Product: CCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccc4)ccc3n2C)c(OC)c1
Yield: 53 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidino-2-methoxyphenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-pentyl chloroformate. Yield: 53% of theory, C35H42N6O6 (642.7); Rf value: 0.54 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=643; (M+H+Na)++=333.4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([O:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Reactant: Cc1ccc(O)cc1
Product: COc1ccc2c(Oc3ccc(C)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 4-methyl-phenol to give (6-methoxy-1-p-tolyloxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[O:16])=[CH:10][CH:9]=2)[CH2:4]1.Cl[C:25]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=1[C:27]#[N:28]>>[CH3:1][N:2]([CH3:23])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:25]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:26]=4[C:27]#[N:28])[CH2:19][CH2:18]3)=[O:16])=[CH:12][CH:13]=2)[CH2:4]1
Reactant: N#Cc1cc(Cl)ccc1Cl
Reactant: CN(C)C1CCN(c2ccc(NC(=O)C3CCNCC3)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)C3CCN(c4ccc(Cl)cc4C#N)CC3)cc2)C1

Procedure:
Piperidine-4-carboxylic acid [4-(3-dimethylaminopyrrolidin-1-yl)phenyl]amide was reacted with 2,5-dichlorobenzonitrile as described in example 323. This resulted in the product with the molecular weight of 452.00 (C25H30CIN5O); MS (ESI): 452 (M+H+).
Reaction SMILES: [Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.P(Br)(Br)[Br:15].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:1][CH2:2][CH2:3][N:4]1[C:8]([CH2:9][Br:15])=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1
Reactant: O=[N+]([O-])c1cc(CO)n(CCBr)n1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To as solution of (1-(2-bromoethyl)-3-nitro-1H-pyrazol-5-yl)methanol (482 mg, 1.93 mmol) in chloroform (20 mL) was cooled to 0° C. was added phosphorus tribromide (522 mg, 0.18 mL, 1.93 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate was (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo to give 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole (469 mg, 78%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10]([C@@H:12]2[CH2:16][C@H:15]([N:17]([CH3:19])[CH3:18])[CH2:14][N:13]2[CH3:20])=O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.CC(C)=O>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C@H:12]3[N:13]([CH3:20])[CH2:14][C@@H:15]([N:17]([CH3:19])[CH3:18])[CH2:16]3)=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)[C@H]1C[C@@H](C(=O)NNc2ccc(F)cn2)N(C)C1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(F)cn23)N(C)C1
Temperature: 60 °C
Yield: 80.3 %

Procedure:
A solution of Intermediate 38b (1.73 g, 6.15 mmol) in THF (40 mL) was treated with triphenyl phospine (3.22 g, 12.3 mmol) and TEA (3.43 mL, 24.6 mmol). Hexachloroethane (2.91 g, 12.3 mmol) was added to the solution portion wise over a period of 5 minutes. The reaction mixture was heated at 60° C. for 16 hours. The reaction mixture was cooled down, treated with acetone to precipitate the triethylammonium chloride, which was then filtered; the filter cake was washed abundantly with acetone and the solvent was evaporated under reduced pressure. The residue was purified by SCX-2 cartridge eluting with DCM (40 mL), MeOH (40 mL) and 2M NH3 in MeOH (40 mL). The product containing fractions were evaporated under reduced pressure to give the title compound as a brown oil (1.3 g, 80%). 1H NMR (300 MHz, d6-DMSO): 201-2.13 (1H, m), 2.2 (3H, s), 2.29 (6H, s), 2.31-2.33 (1H, m), 2.34-2.39 (1H, m), 2.51-2.61 (1H, m), 2.88-2.98 (1H, m), 3.31-3.39 (1H, dd), 3.50 (1H, s), 4.17-4.27 (1H, m), 7.14-7.24 (1H, m), 7.67-7.77 (1H, m), 9.00-9.07 (1H, m).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][CH2:5][C:6]1[O:7][CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=4[CH3:31])[N:21]=[C:20]([NH2:32])[N:19]=3)=[CH:13][CH:12]=2)[N:10]=1.CO.[OH-].[Na+].[ClH:38]>O>[NH2:32][C:20]1[N:19]=[C:18]([NH:17][C:14]2[CH:13]=[CH:12][C:11]([C:9]3[N:10]=[C:6]([CH2:5][CH2:4][C:3]([OH:33])=[O:2])[O:7][CH:8]=3)=[CH:16][CH:15]=2)[CH:23]=[C:22]([C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:21]=1.[ClH:38]
Reactant: COC(=O)CCc1nc(-c2ccc(Nc3cc(-c4cc(Cl)ccc4C)nc(N)n3)cc2)co1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(Cl)cc1-c1cc(Nc2ccc(-c3coc(CCC(=O)O)n3)cc2)nc(N)n1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-{4-[2-amino-6-(5-chloro-2-methyl-phenyl)-pyrimidin-4-ylamino]-phenyl}-oxazol-2-yl)-propionic acid methyl ester (106 mg, 0.21 mmol), methanol (15 ml), and a solution of sodium hydroxide (500 mg, 12.5 mmol) in water (10 ml) was heated to 70° C. for 2 hours. After cooled to room temperature, the reaction mixture was neutralized to pH=1 using concentrated hydrochloric acid. Solid was collected via filtration and dried to give title compound in its hydrochloric acid salt form, (106 mg, 64% in two steps). 1H NMR (DMSO-d6) δ 2.40 (s, 3H, CH3), 2.76 (t, 2H, J=7.0 Hz, CH2), 3.04 (t, 2H, J=7.0 Hz, CH2), 6.57 (br s, 2H, NH2), 7.44 (d, 1H, J=8.2 Hz, Ar), 7.53-7.57 (m, 3H, Ar), 7.67 (d, 2H, J=8.7 Hz, Ar), 7.94-8.00 (m, 2H, Ar).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].C(O)C>C1(C)C=CC=CC=1>[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20][NH:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH3:9])=[CH:6][CH:7]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11]
Reactant: COc1ccc(N)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(OC)nc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 91.5 %

Procedure:
A solution of 3-amino-6-methoxy-pyridine (200.0 g, 1611.05 mmol, 1.0 eq) and 2-ethoxymethylene-malonic acid diethyl ester (348.4 g, 1611.05 mmol, 1.0 eq) in toluene (650 mL) is heated to reflux and the ethanol formed is removed by azeotropic distillation. After 2.5 hours at 115° C., the reaction mixture is cooled to room temperature, the solvent is removed and the resulting solid is washed with 500 mL of hexane then dried under vacuum to afford 2-[(6-methoxy-pyridin-3-ylamino)-methylene]-malonic acid diethyl ester as a red solid (434.0 g, 90% yield).
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[C-:10]#[N:11].[Na+].O>CO>[C:10]([CH2:2][C:3](=[O:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6])#[N:11]
Reactant: COC(=O)CC(=O)CBr
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)CC(=O)CC#N
Temperature: 25 °C

Procedure:
10 g of methyl 4-bromo-3-oxobutanoate is dissolved in 100 g of methanol. The resultant solution is cooled to 0° C. and a solution of 4 g of sodium cyanide in 100 g of methanol is added thereto. After completion of the addition, the mixture is warmed gradually to room temperature under stirring. Thereafter, the reaction mixture is poured into water, and extracted with ethyl acetate. The organic layer is washed with saturated brine, dried, concentrated to obtain methyl 4-cyano-3-oxobutanoate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]([CH3:15])=O.N1CCCCC1>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:13]([CH3:15])[CH3:12]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CC(C)=O
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A mixture of 5-fluoro-1,3-dihydro-indol-2-one (2.84 g, 20 mmol), acetone (2.2 mL, 30 mmol) and piperidine (0.8 mL, 8 mmol) in methanol (100 mL) was heated to reflux for 16 hours. Then the reaction mixture was allowed to cool to room temperature. The solid was collected by filtration, washed with methanol (20 mL) and dried in vacuo to afford 5-fluoro-3-isopropylidene-1,3-dihydro-indol-2-one (2.6 g, 68%) as powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14](O)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2].CN(C=O)C.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O=P(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:10]2[N:11]=[CH:12][C:13]([C:16]#[N:17])=[C:14]([NH:42][C:39]3[CH:38]=[CH:37][C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:41][CH:40]=3)[C:9]2=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc2c(O)c(C#N)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2c(Nc3ccc(Oc4ccccc4)cc3)c(C#N)cnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Compound 406E (110 mg, 0.476 mmol) was heated in POCl3 (1 ml) at 83-100° C. for 2 h. Excess POCl3 was removed on a rotary evaporator, and the residue was stripped with CH2Cl2 (2 ml). To the solid residue was added DMF (5 ml), K2CO3 (690 mg, 5 mmol) and 4-phenoxy-phenylamine (353 mg, 1.91 mmol) at 0° C. The reaction mixture was degassed and stirred at rt overnight. Solid was filtered off and the filtrate was concentrated, the residue was purified by silica gel flash column chromatography to give the 406 (147 mg, 78%) as a yellow solid (25% EtOAc—Hexanes). LCMS Found: (M+H)+=398.6
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]([CH2:9]Br)=[CH:7][C:6]([N+:11]([O-:13])=[O:12])=[N:5]1.[F:14][C:15]([F:19])([F:18])[CH2:16][NH2:17].CS(C)=O>O>[N+:11]([C:6]1[CH:7]=[C:8]2[CH2:9][N:17]([CH2:16][C:15]([F:19])([F:18])[F:14])[CH2:2][CH2:3][N:4]2[N:5]=1)([O-:13])=[O:12]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1cc(CBr)n(CCBr)n1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cc2n(n1)CCN(CC(F)(F)F)C2
Temperature: 120 °C
Yield: 78.3 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 1-(2-bromoethyl)-5-(bromomethyl)-3-nitro-1H-pyrazole 124c (632 mg, 2.0 mmol), 2,2,2-trifluoroethanamine (594 mg, 6.0 mmol), and DMSO (5 mL), and heated at 120° C. for 2 h. The mixture was cooled to room temperature and diluted with water (20 mL). The resulting mixture was extracted with ethyl acetate (3×20 mL). The combiner organic layer was dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silical-gel column chromatography eluting with 50:1 dichloromethane/methanol to afford 134a (392 mg, 78%) as a yellow solid. MS-ESI: [M+H]+ 250.9
Reaction SMILES: COC1C=C([C:11](=O)[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]3CCC[C@H:18]3[CH2:17]2)=O)C=CC=1OC.C(OC(N1CCCCC1C(O)=O)=O)(C)(C)C.[Cl:42][C:43]1[CH:55]=[CH:54][C:46]([C:47]([CH2:49][CH2:50][C:51]([OH:53])=O)=[O:48])=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:47](=[O:48])[CH2:49][CH2:50][C:51]([N:19]2[CH2:20][CH2:21][N:16]3[CH2:14][CH2:13][CH2:12][CH2:11][CH:17]3[CH2:18]2)=[O:53])=[CH:54][CH:55]=1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Reactant: COc1ccc(C(=O)CCC(=O)N2CCN3CCC[C@H]3C2)cc1OC
Agent: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: O=C(CCC(=O)N1CCN2CCCCC2C1)c1ccc(Cl)cc1

Procedure:
463 mg of the title compound were prepared as described for 1-(3,4-dimethoxyphenyl)-4-((S)-hexahydropyrrolo[1,2-a]pyrazin-2-yl)butane-1,4-dione, using 1-(tert-butoxycarbonyl)piperidine 2 carboxylic acid instead of BOC-protected proline and 3-(4-chlorobenzoyl)propanoic acid instead of 3-(3,4-dimethoxybenzoyl)propionic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH2:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH2:29][CH2:30][NH:31][C:13](=[O:15])[C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(Nc2cccc(F)c2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Nc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A mixture of 4-(3-fluorophenylamino)benzoic acid (0.040 g, 0.173 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.040 g; 0.173 mmol), HATU (0.072 g; 0.190 mmol) and N,N-diisopropylethylamine (0.075 mL; 0.432 mmol) in DMF (3 mL), was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and sodium hydrogen sulfate, the organic layer was washed with sodium carbonate, brine, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 1 to 10% ethyl acetate in dichloromethane) to yield 0.027 g (39%) of the title compound as a colourless solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:17]([CH3:29])=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[C:17]([CH3:29])=[N:16][N:15]([C:12]3[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=3)[C:19]=2[CH3:20])=[CH:26][CH:25]=1
Reactant: COc1ccc(-c2c(C)nn(-c3ccc(OCc4ccccc4)cc3)c2C)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C)nn(-c3ccc(O)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 1-(4-benzyloxyphenyl)-4-(4-methoxyphenyl)-3,5-dimethyl-1H-pyrazole (57 mg, 0.15 mmol) in methanol (2 mL) and tetrahydrofuran (3 mL) was flushed with nitrogen. A catalytic amount of palladium on carbon (10% wet) was added, and the reaction was again flushed with nitrogen followed by hydrogen. After the reaction was allowed to stir at room temperature for 1 hour, it was filtered through a pad of Celite and concentrated to give 37 mg of the desired phenol. LC-MS (C18H18N2O2 calculated 294) m/z 295 (M+H).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1.[Cl:17][S:18](O)(=[O:20])=[O:19]>>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:8]3[CH:13]=[C:14]([S:18]([Cl:17])(=[O:20])=[O:19])[CH:15]=[CH:16][C:7]=3[CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1nc2c(c(=O)[nH]1)-c1ccccc1CC2
Product: Cc1nc2c(c(=O)[nH]1)-c1cc(S(=O)(=O)Cl)ccc1CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 41 %

Procedure:
1,2,5,6-tetrahydro-3-methyl-1-oxobenzo[f]quinazoline (5 g, 0.024 mole) was added to chlorosulfonic acid (50 ml, Aldrich) and stirred for 12 hours at room temperature. The reaction mixture was poured over ice (750 g), and the dark brown solid collected by filtration. The solid was washed with water, suspended in water (500 ml), and the pH of the suspension adjusted to 5.00 by addition of sodium bicarbonate. The suspension was filtered, the product washed with H2O and dried under high vacuum at room temperature to give 1,2,5,6-tetrahydro-3-methyl-oxobenzo[f]quinazolin-9-sulfonyl chloride as a light brown solid (3.054 g, 41%). 1H NMR (DMSO-d6, 300 MHz) δ: 2.60 (s, 3H, CH3); 2.90 (s, 4H, Ar CH2); 7.22 (d, J=9 Hz, 1H, Ar); 7.53 (d, J=9 Hz, 1H, Ar); 8.75 (s, 1H, Ar).