Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:15](Cl)(=[O:17])=[O:16].C([O:23][C:24](=[O:30])[C@H:25]([CH:27]([CH3:29])[CH3:28])[NH2:26])(C)(C)C.C(N(CC)CC)C>ClCCl.FC(F)(F)C(O)=O>[CH3:28][CH:27]([CH3:29])[C@H:25]([NH:26][S:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:13][C:14]=2[CH:1]=1)(=[O:17])=[O:16])[C:24]([OH:30])=[O:23]
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1S2)C(=O)O
Reaction time: 2 h
Yield: 17.4 %

Procedure:
The crude thianthrene-2-sulfonyl chloride (1.19 g, 3.77 mmol) was mixed with 0.79 g (3.77 mmol) of (L)-valine-t-butyl ester and triethyl amine (1.58 mL, 11.3 mmol) in 50 mL of dichloromethane. After 2 hours, the reaction was partitioned between 1 M HCl and dichloromethane. The organic phase was washed with saturated sodium carbonate solution, dried over magnesium sulfate, and concentrated to give an oily green solid. This compound (0.46 g, 1.0 mmol) was stirred in 5 mL of trifluoroacetic acid for 1 hour and then concentrated in vacuo. The residue was triturated with diethyl ether to give 0.26 g of the title compound as a fluffy white solid.
Reaction SMILES: C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:16][O:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][C:24]([S:28]([NH:31][C@H:32]3[CH2:36][CH2:35][N:34]([CH2:37][C:38](O)=[O:39])[C:33]3=[O:41])(=[O:30])=[O:29])=[CH:25]2)=[CH:20][CH:19]=1.[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[NH2:49]>C1COCC1.CN(C=O)C>[NH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][C:48]=1[NH:49][C:38](=[O:39])[CH2:37][N:34]1[CH2:35][CH2:36][C@H:32]([NH:31][S:28]([C:24]2[CH:23]=[CH:22][C:21]3[C:26](=[CH:27][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)[CH:25]=2)(=[O:29])=[O:30])[C:33]1=[O:41]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CC(=O)O)C3=O)cc2c1
Reactant: Nc1ccncc1N
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(CC(=O)Nc4ccncc4N)C3=O)cc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44.6 %

Procedure:
Triethylamine (0.13 g, 1.3 mmol) and isobutyl chloroformate (0.18 g, 1.3 mmol) are added to a solution of [3-(S)-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxopyrrolidin-1-yl]-acetic acid (0.5 g, 1.3 mmol) in THF (15 mL) at −10° C. The mixture is stirred for 20 minutes then treated with a solution of 3,4-diaminopyridine (0.16 g, 1.5 mmol) in DMF (5 mL). The resulting mixture is warmed to room temperature and stirred for 3 hours. The reaction mixture is concentrated in vacuo, then diluted with methylene chloride. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (5-8% MeOH/CH2Cl2). to give the title compound (0.27 g, 0.58 mmol) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C(OC(=O)[N:28]([C:38]1[CH:43]=[CH:42][C:41]([CH:44]=O)=[C:40]([F:46])[N:39]=1)[CH2:29][C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)(C)(C)C.IC1C2C(=NC=CC=2)N([Si](C(C)C)(C(C)C)C(C)C)C=1.C(OC(=O)N(CC1C(F)=CC=C(NS(CCC)(=O)=O)C=1F)C1C=CC(C=O)=CN=1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:44][C:41]3[CH:42]=[CH:43][C:38]([NH:28][CH2:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:39][C:40]=3[F:46])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2ccc(C=O)c(F)n2)cn1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Agent: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Agent: CCCS(=O)(=O)Nc1ccc(F)c(CN(C(=O)OC(C)(C)C)c2ccc(C=O)cn2)c1F
Product: COc1ccc(CNc2ccc(Cc3c[nH]c4ncc(Cl)cc34)c(F)n2)cn1

Procedure:
respectively, were prepared following the protocol of Scheme 178. P-0259 was prepared by replacing 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine 96 with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine in Step 1 (MS [M+H+]+=506.1). P-0378 was prepared by replacing [2,6-difluoro-3-(propane-1-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 560 with (6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 572 (prepared as described in Example 60, Scheme 177) in Step 1 (MS [M+H+]+=364.1). P-0379 was prepared by replacing both azaindole 96 with 5-chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine and aldehyde 560 with aldehyde 572 in Step 1 (MS [M+H+]+=400.0).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O:14]CC1C=CC=CC=1)=[O:13])[CH3:3].C(O)C.O.C([O-])(O)=O.[Na+:31]>O1CCOCC1.[Pd]>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](=[O:22])[CH:8]2[C:12]([O-:14])=[O:13])[CH3:3].[Na+:31]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)C(=O)CC12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: CC(O)C1C(=O)N2C(C(=O)[O-])C(=O)CC12
Reaction time: 1 h

Procedure:
Benzyl 6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (30 mg) is dissolved in dioxane (2 ml). The solution is treated with ethanol (0.5 ml), H2O (0.5 ml), NaHCO3 (8.5 mg) and 10% Pd/C (20 mg) and the resulting mixture is hydrogenated at 40 psi for 1 hr. The mixture is filtered to remove the catalyst which is washed with H2O (2.5 ml). The combined filtrate is extracted with ethyl acetate (3×2 ml), concentrated in vacuo, and lyophilized to provide sodium 6-(1-hydroxyethyl)-1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH:13]([CH3:15])[CH3:14])[C:11]([CH3:16])=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]2)=[CH:20][CH:19]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO.C(Cl)Cl>[S:30]([N:27]1[CH2:28][CH2:29][N:24]([C:21]2[CH:20]=[CH:19][C:18]([NH:1][C:2]3[N:7]=[C:6]([C:8]4[N:12]([CH:13]([CH3:14])[CH3:15])[C:11]([CH3:16])=[N:10][CH:9]=4)[CH:5]=[CH:4][N:3]=3)=[CH:23][CH:22]=2)[CH2:25][CH2:26]1)([CH3:33])(=[O:31])=[O:32]
Reactant: Cc1ncc(-c2ccnc(N)n2)n1C(C)C
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Solvent: CO
Solvent: ClCCl
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(S(C)(=O)=O)CC4)cc3)n2)n1C(C)C
Temperature: 95 °C

Procedure:
2-Amino-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Method 39 of WO 03/076436; 220 mg, 1 mmol), 1-bromo-4-(4-mesylpiperazinyl)benzene (WO 2001062742; 319 mg, 1 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 2 mol %), 2-(di-tert-butylphosphino)biphenyl (6 mg, 2 mol %) and sodium tert-butoxide (135 mg, 1.4 mmol) in anhydrous 1,4-dioxane (10 ml) was evacuated and refilled with nitrogen (3 times). The reaction was heated under nitrogen at 95° C. overnight before evaporating under reduced pressure. The residue was triturated with EtOAc (20 ml), filtered and re-evaporated to give a gum. Chromatography on silica gel with MeOH:DCM (2:98 to 5:95) gave the title compound as a yellow solid. (70 mg 15%). NMR: 1.39 (d, 6H), 2.47 (s, 3H), 2.92 (s, 3H), 3.17 (m, 4H), 3.26 (m, 4H), 5.70 (septuplet, 1H), 6.92 (d, 2H), 6.94 (d, 1H), 7.39 (s, 1H), 7.48 (d, 2H), 8.32 (d, 1H), 9.18 (s, 1H); m/z 456.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]=[C:11]=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:13]1([CH3:22])[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[NH2:21]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:21][C:14]2[C:15]([CH3:20])=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=2[CH3:22])=[S:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: O=[N+]([O-])c1cccc(N=C=S)c1
Solvent: CO
Product: Cc1cc(C)c(NC(=S)Nc2cccc([N+](=O)[O-])c2)c(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2.25 g (12.5 mmol) of 3-nitrophenylisothiocyanate and 1.4 mL (10 mmol) of mesityl amine in 10 mL of methanol was stirred at room temperature for 2 h. The resulting precipitate was collected by filtration and dried to give a quantitative yield of 1-(3-nitrophenyl)-3-(mesityl)thiourea. To 1.8 g (5.7 mmol) of the thiourea thus prepared slurried in 20 mL of CCl4 was added 0.35 mL (6.9 mmol) of bromine. The mixture was heated at reflux for 4 h, allowed to cool to room temperature and diluted with dichloromethane. This solution was washed successively with saturated sodium bicarbonate, water and brine before being dried over sodium sulfate. The solution was filtered, concentrated in vacuo and the resulting crude title compound was obtained in quantitative yield and was used without further purification.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Br[CH2:7]/[CH:8]=[CH:9]/[CH2:10]Br>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:4][CH3:5])[CH2:7]/[CH:8]=[CH:9]/[CH2:10][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: BrC/C=C/CBr
Reactant: CCNCC
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCN(CC)C/C=C/CN(CC)CC
Yield: 82.7 %

Procedure:
The synthesis of the free base was carried out by the general procedure of J. J. Roberts and W. C. J. Ross (J. Chem. Soc., 1952, 4288). Diethylamine (3.285 g, 0.045 mol) was added during 15 min to a cooled solution (0° C.) of (E)-1,4-dibromobut-2-ene (1.07 g, 0.005 mol) (1) in benzene (5 ml). The product was diluted with chloroform (25 ml) and the organic layer was washed with water (4×25 ml). The chloroform layer was dried, filtered, and concentrated in vacuo to give (E)-N,N,N',N'-tetra-ethyl-1,4-diaminobut-2-ene as an oil (0.82 g, 82%). δH (90 MHz, CDCl3) 1.10 (12H, t), 2.60 (8H, q), 3.20 (4H, m) and 5.75 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](I)=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8].[O:14]1[CH2:18][CH2:17][NH:16][C:15]1=[O:19].[C@H]1(N)CC[C@H](N)CC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[CH2:17][CH2:18][O:14][C:15]2=[O:19])=[C:6]([CH:12]=1)[C:7]([N:9]([CH3:11])[CH3:10])=[O:8]
Reactant: CN(C)C(=O)c1cc(Br)ccc1I
Reactant: O=C1NCCO1
Agent: [Cu]I
Agent: N[C@H]1CC[C@H](N)CC1
Agent: O=P([O-])([O-])[O-]
Product: CN(C)C(=O)c1cc(Br)ccc1N1CCOC1=O
Yield: 64.7 %

Procedure:
A microwave vial was charged with 5-bromo-2-iodo-N,N-dimethyl-benzamide (200 mg, 0.74 mmol), 2-oxazolidinone (77.4 mg, 0.89 mmol), copper(I)-iodide (70.5 mg, 0.04 mmol), trans-1,4-cyclohexanediamine (84.6 mg, 0.74 mmol), and potassium phosphate (377.2 mg, 1.78 mmol) and degassed dioxane (2 ml) added. The reaction mixture was irradiated to 150° C. for 1 hour in a microwave reactor. The solvent was evaporated and the resulting solid purified by silica gel chromatography to give 5-bromo-N,N-dimethyl-2-(2-oxo-oxazolidin-3-yl)-benzamide as a white solid (150 mg, 65% yield). MS: m/z 315.4 (M+H+).
Reaction SMILES: C1C=CC=CC=1.[C:7]([O:11][CH2:12][CH3:13])(=[O:10])[CH:8]=[CH2:9].C1(C=CC(O)=CC=1)O.O=O.[C:24]([O:34]CC)(=[O:33])[CH:25]=CC1C=CC=CC=1.C1(C(C2C=CC=CC=2)=CC(OCC)=O)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(=O)C>[C:24]([O:34][CH:9]=[CH:8][C:7]([O:11][CH2:12][CH3:13])=[O:10])(=[O:33])[CH3:25]
Reactant: CCOC(=O)C=Cc1ccccc1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOC(=O)C=C(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C=COC(C)=O

Procedure:
In a flask, 15 mmol of benzene, 2 mmol of ethyl acrylate, 0.1 mmol of palladium(II) acetate, 0.4 mmol of hydroquinone, 0.02 mmol of H7PMo8V4O40, and 5 ml of acetic acid were placed and were stirred at a constant temperature of 90° C. in an atmosphere of oxygen gas at 1 atm (0.1 MPa) for 15 hours. The resulting reaction mixture was analyzed by gas chromatography to find that ethyl cinnamate, ethyl 3,3-diphenylacrylate, and ethyl 3-acetoxyacrylate were produced in yields of 26%, 2%, and 9%, respectively.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:36][C@H:35]([OH:37])[CH2:34]1)([CH3:29])([CH3:28])[CH3:27]>O1CCCC1.CCOC(C)=O>[C:26]([O:30][C:31](=[O:38])[NH:32][C@H:33]1[CH2:36][C@H:35]([O:37][C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=4)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=3[N:7]=[C:2]([Cl:1])[N:3]=2)[CH2:34]1)([CH3:29])([CH3:27])[CH3:28]
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccccn2)c2c(Cl)nc(Cl)nc21
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@H](Oc2nc(Cl)nc3c2c(-c2ccccn2)cn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (318 mg, 0.804 mmol) in tetrahydrofuran (8 mL) was added tert-butyl(trans-3-hydroxycyclobutyl)carbamate and potassium hexamethyldisilizane (642 mg, 3.2 mmol) and the mixture stirred at ambient temperature for 1 hr. The reaction mixture was diluted with EtOAc (10 mL) and washed with water (20 mL). The aqueous layer was extracted with EtOAc (three×10 mL) and the combined organics were dried over MgSO4, filtered and stripped to give the title compound (485 mg, 110 yield). The crude material was used for the next step. m/z (APCI+) for C17H33N5O4ClSi 546.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].[CH3:27][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([O:14][CH3:27])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1O
Yield: 96.4 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (0.800 g, 2.21 mmol) was dissolved in a mixed solvent of methanol (4 ml) and benzene (28 ml) and after adding thereto trimethylsilyldiazomethane (10% hexane solution) (0.303 g, 2.65 mmol), the solution was stirred at room temperature for 3 hours. The reaction solution was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=3:1) to obtain the titled compound (0.800 g, 2.13 mmol, 96%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[C:10]1([CH:16]([NH2:26])[C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH:16]([C:17]2[NH:25][C:20]3=[CH:21][N:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[NH:26][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NC(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: O=C(O)c1ccccn1
Product: O=C(NC(c1ccccc1)c1cc2ccncc2[nH]1)c1ccccn1
Yield: 6 %

Procedure:
Using the procedure described for Example 43 with picolinic acid at room temperature, the reaction was stopped once 1-phenyl-1-(1H-pyrrolo[2,3-c]pyridin-2-yl)methylamine was consumed as judged by TLC analysis. Purification by Biotage chromatography provided N-[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methyl]-2-pyridinecarboxamide (8 mg, 6%) as an off-white solid: mp 102-110° C.; 1H NMR (300 MHz, CD3OD) δ 6.42 (1H, s), 6.64 (1H, s), 7.36-7.62 (7H, m), 7.98-8.03 (2H, m), 8.13-8.16 (1H, m), 8.59 (1H, s), 8.63-8.67 (1H, m); ESI MS m/z 329 [C20H16N4O+H]+; HPLC (Method A) >99% (AUC) tR=15.8 min.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>C(O)(=O)C>[F:12][C:13]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:14]=1[N:15]1[C:1](=[O:11])[C:2]2[CH2:10][CH2:9][CH2:8][CH2:7][C:3]=2[C:4]1=[O:6]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(CCCC2)C(=O)N1c1ccc(F)cc1F
Reaction time: 1 h

Procedure:
A solution of 5 parts of 3,4,5,6-tetrahydrophthalic anhydride in 100 parts of glacial acetic acid was treated with 4.3 parts of 2,4-difluoroaniline at once and stirred for one hour. After refluxing for 20 hours, the reaction mixture was poured over 200 parts of ice. The resulting crystals were filtered and recrystallized from 70 parts of methanol at -40°C to yield 5 parts off-white crystals of 2-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione melting at 73°-74°C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:14])[C:6]2[CH:12]=[C:11]([F:13])[CH:10]=[N:9][C:7]=2[N:8]=1.CCN(C(C)C)C(C)C.[C:24]1([CH2:30][CH2:31][C:32](Cl)=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOC(C)=O>[F:13][C:11]1[CH:10]=[N:9][C:7]2[N:8]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:4][C:5](=[O:14])[C:6]=2[CH:12]=1
Reactant: NCc1nc2ncc(F)cc2c(=O)[nH]1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NCc1nc2ncc(F)cc2c(=O)[nH]1
Yield: 1.9 %

Procedure:
A solution of 2-aminomethyl-6-fluoro-3H-pyrido[2,3-d]pyrimidin-4-one (130 mg, 0.67 mmol) in THF (5 ml) was treated with DIPEA (173 mg, 1.34 mmol) and 3-phenyl-propionyl chloride (136 mg, 0.80 mmol) at 0° C. for 18 hours. The reaction mixture was diluted with EtOAc, washed with water and brine. The organic layers were dried over MgSO4, filtrated, evaporated and chromatographed (silica gel, EtOAc/heptane, 1/1) to yield N-(6-fluoro-4-oxo-3,4-dihydro-pyrido[2,3-d]pyrimidin-2-ylmethyl)-3-phenyl-propionamide (6 mg, 13 μmol; 2%) as yellow solid. MS (m/e): 327.3 [M+H+].
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17](O)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[CH2:1]([N:8]1[C:12]2=[C:13]([N:20]3[CH2:29][CH2:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21]3)[N:14]=[C:15]([C:17]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:18])[CH:16]=[C:11]2[CH:10]=[C:9]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2cc(C(=O)O)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Product: Cc1cc2cc(C(=O)N3CCN(C)CC3)nc(N3CCc4ccccc4C3)c2n1Cc1ccccc1
Yield: 57 %

Procedure:
In accordance with the same procedures as in Step 1 of Example 756, except for using 1-benzyl-7-(3,4-dihydro-1H-isoquinolin-2-yl)-2-methyl-1H-pyrrolo[2,3-c]pyridin-5-carboxylic acid prepared in Step 1 and 1-methylpiperazine, the titled compound was obtained as a white solid. (Yield: 57%)
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CC=1.ClC1C=CC(OCC#N)=CC=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([N+:56]([O-:58])=[O:57])=[C:51]([CH2:53][C:54]#[N:55])[CH:52]=1.[F:59][C:60]1[CH:61]=[C:62]([CH:65]=[CH:66][CH:67]=1)[CH2:63]Br>C(#N)C>[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([N+:56]([O-:58])=[O:57])=[C:51]([CH2:53][C:54]#[N:55])[CH:52]=1.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([N+:56]([O-:58])=[O:57])=[C:51]([CH:53]([CH2:63][C:62]2[CH:65]=[CH:66][CH:67]=[C:60]([F:59])[CH:61]=2)[C:54]#[N:55])[CH:52]=1
Reactant: Fc1cccc(CBr)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#CCOc1ccc(Cl)cc1
Agent: N#CCc1cc(Cl)ccc1[N+](=O)[O-]
Solvent: CC#N
Product: N#CC(Cc1cccc(F)c1)c1cc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(5-Chloro-2-nitrophenyl)acetonitrile was prepared from 4-chloronitrobenzene and 4-chlorophenoxyacetonitrile according to procedure known in the art (M. Makosza, J. Winiarski, J. Org. Chem. 1984, 49, 1494). To a suspension of 13.8 g (0.1 mol) anhydrous potassium carbonate in 100 ml acetonitrile were added 100 mg 18-crown-6, 3.93 g (20.0 mmol) of (5-chloro-2-nitrophenyl)acetonitrile, and 4.15 g (21.95 mmol) 3-fluorobenzyl bromide, successively. It was stirred at room temperature overnight, and the solids were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was stirred with a small amount of ethanol to give the pale yellow crystalline title compound, which was collected by filtration, washed with cold ethanol, and dried in vacuo.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([Cl:18])=[C:13]([Cl:17])[CH:14]=2)[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Solvent: ClCCl
Solvent: CO
Product: O=CCC1Cc2cc(Cl)c(Cl)cc2C1=O
Reaction time: 0.75 h
Yield: 73 %

Procedure:
An ozone stream (3.5 g ozone/hour) was conducted for 45 minutes while stirring through a solution, cooled to -70°, of 10.8 g of (RS)-2-(2-buten-1-yl)-5,6-dichloro-1-indanone in 150 ml of anhydrous dichloromethane and 30 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.66 ml of dimethyl sulfide, the mixture was stirred at room temperature for 3 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 150 ml of dichoromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 100 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. There were obtained 11.6 g of crude product which was crystallized from hexane/ethyl acetate. The crystallization gave 7.59 g (73%) of (RS)-2-(2-oxoethyl)-5,6-dichloro-1-indanone as a light yellow solid with m.p. 93°-96°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]OS(C)(=O)=O)[CH:5]=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl.[F:23][C:24]1([F:29])[CH2:28][CH2:27][NH:26][CH2:25]1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]#[C:9][CH2:10][N:26]2[CH2:27][CH2:28][C:24]([F:29])([F:23])[CH2:25]2)[CH:3]=1
Reactant: FC1(F)CCNC1
Reactant: CS(=O)(=O)OCC#Cc1cncc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: FC1(F)CCN(CC#Cc2cncc(Br)c2)C1
Temperature: 80 °C

Procedure:
To a solution of methanesulfonic acid 3-(5-bromo-pyridin-3-yl)-prop-2-ynyl ester (Intermediate 223) (1 eq, 1.95 mmol, 566 mg) in DMF (6 ml) are added K2CO3 (2.5 eq, 4.88 mmol, 674 mg) and 3,3-difluoro-pyrrolidine hydrochloride (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.2 eq, 2.34 mmol, 336 mg). The resulting mixture is heated at 80° C. for 2 h. The reaction mixture is cooled to r.t. before adding water and extracting the mixture with EtOAc. The organic layer is dried with MgSO4, filtered, and the solvents are removed in vacuo. Purification by column chromatography yields the title compound; [M+H]+=301/303.