Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.[Na].[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16]Cl>CO>[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH2:16][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1
Reactant: OCc1ccc(O)cn1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Agent: [Na]
Solvent: CO
Product: OCc1ccc(OCc2cccc(Cl)c2)cn1
Reaction time: 0.42 h

Procedure:
The solution of 16.2 g of 5-hydroxy-2-pyridinemethanol hydrochloride in 150 ml of methaol is added to a solution of 4.6 g of sodium in 250 ml of methanol, while stirring, over a period of 25 minutes. The solution is stirred for one hour and then a solution of 19.3 g of m-chlorobenzyl chloride in 50 ml of methanol is added. Then the mixture is refluxed for 19 hours, cooled, filtered and the filtrate evaporated to a residue. The residue is suspended in 100 ml of water, made basic with 20% aqueous sodium hydroxide solution and then extracted with chloroform. The chloroform extract is separated, dried over sodium sulfate, filtered and the filtrate evaporated, to yield 5-(m-chlorobenzyloxy)-2-pyridinemethanol melting at 78°-80°.
Reaction SMILES: [H-].[Na+].C(OP([CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=O)[CH2:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C1COCC1>[C:18]1([CH:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:25]2[CH2:28][C:27](=[C:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Sodium hydride (60%, 202 mg, 5.06 mmol) was suspended in anhydrous THF (15 mL) and cooled in an ice bath. Ethyl 2-(diethoxyphosphoryl)propanoate (1.2 g, 5.06 mmol) was added dropwise under nitrogen and the mixture was stirred in an ice bath for 1 h. 1-(Diphenylmethyl)azetidin-3-one (1 g, 4.21 mmol) was added in portions as a solid and the mixture was stirred at room temperature for 1 h, then left to stir at room temperature overnight. Water (50 mL) was added and the mixture was extracted with DCM (3×50 mL). Brine was added, and the aqueous and organic layers were separated. The organic layer was dried over sodium sulfate and concentrated. The resulting crude yellow oil was purified by FCC, eluting with 0-50% EtOAc, to afford a clear oil which crystallised upon standing. The solids were sonicated with heptane and the remaining solid was collected by filtration. The filtrate was concentrated and sonicated with heptane to afford a second crop of solid. The filtrate was concentrated and the residue was sonicated with heptane to afford a further crop of solid material. The resultant solids were collected and combined to afford the title compound (892 mg, 66%) as a white solid. δH (250 MHz, CDCl3) 7.56-7.39 (m, 4H), 7.38-7.15 (m, 6H), 4.63-4.45 (m, 1H), 4.24-4.01 (m, 4H), 3.96-3.76 (m, 2H), 1.72-1.58 (m, 3H), 1.27-1.14 (m, 3H).
Reaction SMILES: [CH:1]1([O:7][C:8]([O:10][CH:11](I)[CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1/[CH:24]=[CH:25]\[S:26][C:27]1[C@H:28]([CH3:41])[C@@H:29]2[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:30]2[C:31]=1[C:32]([O-:34])=[O:33].[Na+]>CCCCCC.CN(C)C(=O)C>[OH:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:20]=[CH:21][S:22][C:23]=1/[CH:24]=[CH:25]\[S:26][C:27]1[C@H:28]([CH3:41])[C@@H:29]2[C@@H:36]([C@H:37]([OH:39])[CH3:38])[C:35](=[O:40])[N:30]2[C:31]=1[C:32]([O:34][CH:11]([O:10][C:8]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9])[CH3:12])=[O:33]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3COCCO)[C@H](C)[C@H]12
Reactant: CC(I)OC(=O)OC1CCCCC1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: CC(OC(=O)OC1CCCCC1)OC(=O)C1=C(S/C=C\c2scnc2COCCO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h
Yield: 20969.6 %

Procedure:
A solution (2 ml) of 0.147 mg of 1-(cyclohexyloxycarbonyloxy)ethyl iodide in hexane was added to a solution of 51.8 mg of sodium (1R,5S,6S)-2-[[(Z)-2-[4-(2-hydroxyethoxy)methylthiazol-5-yl]ethen-1-yl]thio]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate in 2 ml of N,N-dimethylacetamide under an argon atmosphere at −10° C. The mixture was stirred at the same temperature for one hr, and 2 ml of hexane was then added to the reaction solution, followed by separation into an upper layer and a lower layer. Brine was added to the lower layer, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure, and the residue was purified by column chromatography on silica gel (chloroform:methanol=20:1) to give 61.7 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:21][CH2:20][C:14]2[N:15]=[N:16][C:17](Cl)=[CH:18][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:21][CH2:20][C:14]2[N:15]=[N:16][C:17]([NH:23][NH2:24])=[CH:18][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(OCc1ccccc1)N1CCc2nnc(Cl)cc2C1
Solvent: O
Product: NNc1cc2c(nn1)CCN(C(=O)OCc1ccccc1)C2

Procedure:
19.2 g of crude oily 3-chloro-5,6,7,8-tetrahydro-6-pyrido[4,3-c]pyridazinecarboxylic acid benzyl ester and 100 cc of hydrazine hydrate are stirred at a bath temperature of 70° for 71/2 hours, and the mixture is worked up to the crude title compound in a manner analogous to that described in Example 37, and this compound is recrystallized from acetonitrile. M.P. 135°-137° (decomp.).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:54][CH2:55][CH2:56][CH3:57])=[C:41]([C:43]2[NH:48][C:47](=[O:49])[C:46]([CH2:50][CH3:51])=[C:45]([CH2:52][CH3:53])[N:44]=2)[CH:42]=1>ClCCl>[CH2:52]([C:45]1[N:44]=[C:43]([C:41]2[CH:42]=[C:37]([NH:36][C:12]([CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:14])[CH:38]=[CH:39][C:40]=2[O:54][CH2:55][CH2:56][CH3:57])[NH:48][C:47](=[O:49])[C:46]=1[CH2:50][CH3:51])[CH3:53]
Reactant: CCCOc1ccc(N)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCOc1ccc(NC(=O)CCCNC(=O)OC(C)(C)C)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
N-Boc-4-aminobutyric acid (203 mg, 1 mmol) was dissolved in dichloromethane (50 ml), and added with EDCI (180 mg, 1 mmol) and HOBT (135 mg, 1 mmol), followed by stirring at room temperature for 12 h. The compound of example 42 (300 mg, 1 mmol) was added thereinto and the stirring continued at room temperature for 6 h. The reaction mixture was washed with water (50 ml) and saturated saline (50 ml) respectively. The organic layer was dried with anhydrous sodium sulfate, and concentrated, and the residue was passed through a silica gel column to give the white title compound (200 mg, yield: 41%). 1H NMR (CDCl3) δ: 9.00 (1H, br), 8.39 (1H, d), 8.09 (1H, dd), 6.99 (1H, d), 4.83 (1H, t), 4.14 (2H, t), 3.27 (2H, m), 2.65 (2H, q), 2.59 (2H, q), 2.41 (2H, t), 1.97 (2H, m), 1.89 (2H, m), 1.48 (9H, s), 1.29 (3H, t), 1.14 (3H, t), 1.13 (3H, t).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:11])[CH:9]=[CH2:10].C(N(CC)C(C)C)(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C>[C:4]([O:11][CH2:8][CH:9]=[CH2:10])(=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: C=CCO
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)CCC(=O)O
Reaction time: 1 h

Procedure:
To a solution of commercially available succinic anhydride (2.00 g, 20.0 mmol) in dichloromethane (10 ml) were added allyl alcohol (1.75 g, 30.1 mmol), N,N-diisopropylethylamine (3.88 g, 30.1 mmol) and 4-(N,N-dimethylamino)pyridine (10 mg) at room temperature. The mixture was stirred for 1 hour, then 1N hydrochloric acid was added thereto, and the resulting solution was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to afford crude allyl hydrogen succinate.
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Li]CCCC.C([O:25][B:26](OC(C)C)[O:27]C(C)C)(C)C.Cl>C1COCC1.CCOCC>[CH3:1][C:2]1([C:8]2[CH:13]=[C:12]([B:26]([OH:27])[OH:25])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc(Br)cc1C1(C)CCCCC1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1C1(C)CCCCC1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
To a mixture of 2-(1-methylcyclohexyl)-4-bromoanisole (13.66 g, 0.0482 mol) in THF (121 mL) cooled to −75° C. under an atmosphere of argon was added n-BuLi (33.2 mL, 1.6 M, 0.053 mol) dropwise maintaining a temperature below −70° C. The resulting suspension was stirred for 30 minutes and triisopropylborate (34.2 mL, 27.87 g, 0.148 mol) was added dropwise. The mixture was allowed to warm to RT overnight. The resulting mixture was cooled to 0° C. and 1.0 N HCl (150 mL) was slowly added. After warming to RT the mixture was diluted with ether and the layers separated, the aqueous layer was extracted ether (3×) and the organic layers combined. The resulting organic layer was washed with water, brine and dried (Mg2SO4). The mixture was filtered, evaporated and the resulting yellow oil was purified on silica gel (eluent: CH2Cl2:MeOH, 100 to 92:2) to afford 3-(1-methylcyclohexyl)-4-methoxyphenyl boronic acid (7.72 g, 64%) as a white solid. 1H NMR (300 MHz; DMSO-d6): δ 120 (s, 3H), 1.40–1.85 (m, 8H), 2.00–2.10 (m, 2H), 3.75 (s, 3H), 6.90 (d, J=8.4 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.66 (brs, 1H), 7.81 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][NH:14][C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9].[CH3:24][S:25]([N:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][CH:35]2[C:38]([O-])=[O:39])[CH2:30][CH2:29]1)(=[O:27])=[O:26].[Li+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([C@H:11]1[CH2:15][N:14]([C:38]([CH:35]2[CH2:36][CH2:37][N:34]2[CH:31]2[CH2:32][CH2:33][N:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:29][CH2:30]2)=[O:39])[C@H:13]([C:16]([NH:18][C:19]2([C:22]#[N:23])[CH2:21][CH2:20]2)=[O:17])[CH2:12]1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)N1CCC(N2CCC2C(=O)[O-])CC1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2)CC1
Agent: [Li+]
Product: CS(=O)(=O)N1CCC(N2CCC2C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)CC1

Procedure:
The reaction of (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)pyrrolidine-2-carboxamide 7H and lithium 1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carboxylate 20L carried out according to the general procedure L yielded (2S,4R)-4-(2-chlorophenylsulfonyl)-N-(1-cyanocyclopropyl)-1-(1-(1-(methylsulfonyl)piperidin-4-yl)azetidine-2-carbonyl)pyrrolidine-2-carboxamide 1:1 epimers as a light brown solid (quant.). MS ISP (m/e): 598.1 (100) [(M+H)]]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[CH:4][N:3]=1.[F:15][CH:16]([F:37])[CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)=[O:20]>>[F:15][CH:16]([F:37])[CH2:17][NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]3[CH3:14])[CH:5]=[CH:4][N:3]=2)=[CH:24][CH:23]=1)=[O:20]
Reactant: C[C@H]1COCCN1c1ccnc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NCC(F)F)cc2)OC1(C)C
Product: C[C@H]1COCCN1c1ccnc(-c2ccc(NC(=O)NCC(F)F)cc2)n1

Procedure:
Method as described for example 49 using (S)-4-(2-chloropyrimidin-4-yl)-3-methylmorpholine (intermediate 3) and 1-(2,2-difluoroethyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 20). Purified by prep HPLC at high pH to afford the title compound. (68 mg, 38%).
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C@@H:25]1[C@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:29]([CH3:48])[O:28][C@H:26]1[OH:27])(=[O:3])[CH3:2].[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]#[N:52].C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[Cl:49][C:50]([Cl:54])([Cl:53])[C:51]([O:27][C@@H:26]1[O:28][C@@H:29]([CH3:48])[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:25]1[O:24][C@@H:6]1[O:7][C@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]1[NH:4][C:1](=[O:3])[CH3:2])=[NH:52]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)N[C@H]1[C@H](O[C@@H]2[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](C)O[C@H]2O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)N[C@H]1[C@H](O[C@H]2[C@H](OC(=N)C(Cl)(Cl)Cl)O[C@@H](C)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The hemiacetal 320 (541 mg, 0.80 mmol) was dissolved in CH2Cl2 (20 mL), placed under argon and cooled to 0° C. Trichloroacetonitrile (0.810 mL, 8 mmol), then DBU (10 μL, 80 μmol) were added. The mixture was stirred at 0° C. for 1 h. The mixture was concentrated and toluene was co-evaporated from the residue. The residue was eluted from a column of silica gel with 1:1 cyclohexane-EtOAc and 0.2% of Et3N to give 307 (560 mg, 86%) as a colourless foam; [α]D+2° (c 1, CHCl3). 1H NMR: δ 8.56 (s, 1H, NH), 7.50-7.20 (m, 10H, Ph), 6.29 (d, 1H, J1,2=1.3 Hz, H-1A), 5.50 (d, 1H, J2,NH=8.3 Hz, NHD), 5.17 (pt, 1H, J2,3=J3,4=9.5 Hz, H-3D), 5.09 (dd, 1H, J4,5=9.5 Hz, H-4D), 4.85-4.60 (m, 4H, CH2Ph), 4.68 (d, 1H, J1,2=8.0 Hz, H-1D), 4.22-4.10 (m, 2H, J5,6=5.0, J6a,6b=12.2 Hz, H-6aD, 6bD), 4.00 (m, 1H, H-2D), 3.99 (dd, 1H, J2,3=3.5 Hz, H-2A), 3.90 (dq, 1H, J4,5=9.6, J5,6=6.2 Hz, H-5A), 3.89 (dd, 1H, J3,4=9.5 Hz, H-3A), 3.62 (m, 1H, H-5D), 3.50 (dd, 1H, H-4A), 2.02, 2.00, 1.98 (3s, 9H, OAc), 1.65 (s, 3H, NHAc), 1.32 (d, 3H, H-6A); 13C NMR: δ 171.2, 171.0, 170.4, 169.6 (C═O), 160.5 (C═NH), 138.2-128.0 (Ph), 103.3 (C-1D), 97.3 (C-1A), 91.4 (CCl3), 80.3 (C-4A), 79.9 (C-3A), 77.5 (C-2A), 76.0, 73.8 (2C, CH2Ph), 73.1 (C-3D), 72.2 (C-5D), 71.1 (C-5A), 68.8 (C-4D), 62.5 (C-6D), 54.8 (C-2D), 23.3 (NHAc), 21.4, 21.1, 21.0 (3C, OAc), 18.4 (C-6A) Anal. Calcd for C36H43Cl3N2O13: C, 52.85; H, 5.30; N, 3.42. Found: C, 52.85; H, 5.22; N, 3.47.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])C=C1.N[C:9]1[CH:14]=[CH:13][CH:12]=CN=1>C(O)(=O)C>[CH3:12][C:13]1=[C:14]([CH3:9])[C:4]([O:6][C:1]1=[O:7])=[O:5]
Reactant: Nc1ccccn1
Reactant: O=C1C=CC(=O)O1
Solvent: CC(=O)O
Product: CC1=C(C)C(=O)OC1=O
Yield: 269.6 %

Procedure:
58.0 g (0.5 mol) of maleic anhydride and 4.7 g (0.05 mol) of 2-aminopyridine are boiled under reflux for 48 hours in 200 ml of glacial acetic acid. Working up as in Example 1 affords 17.0 g (54%) of dimethylmaleic anhydride with a melting point of 91°-93° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:15])[NH:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1>N1C=CC=CC=1>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[O:15])[NH:13][C:11](=[O:12])[C:10]2=[CH:16][CH:17]=1)(=[O:4])=[O:3]
Reactant: Nc1ccc2c(c1)C(=O)NC2=O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc2c(c1)C(=O)NC2=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
Methanesulfonylchloride (2.6 ml, 0.034 mol) was added dropwise to a stirred suspension of 4-aminophthalimide (5.0 g, 0.031 mol) in pyridine (50 ml). The mixture was stirred for 48 h under N2 at room temperature, after which time the solid formed was isolated by filtration, washing well with H2O and CH2Cl2 and then dried in vacuo to afford the subtitle compound as a colourless solid (5.67 g, 76%). Rf 0.52 (CH2Cl2/MeOH/0.88NH3 90/10/1, v/v). MS m/z 241 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:22]1>CCCCO.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:22]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccccn1
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccccn4)c23)C1

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide (194 mg, 0.579 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.348 g, 1.74 mmol) in n-BuOH (2 mL) was stirred at 149° C. for 24 hours in a sealed tube and concentrated in vacuo. The residue obtained was dissolved in ethyl acetate (20 mL) and successively washed with water (10 mL) and brine (10 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+) on Biotage SP4 unit eluting with gradient of 10-90% CH3CN/water to provide (R)-tert-butyl 1-(5-bromo-3-(picolinamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate. This material was dissolved in DCM (3 mL), treated with TFA (0.5 mL) and stirred at room temperature for 1 hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in DCM (1 mL) and treated with 2N HCl in ether (3 mL). The solid formed was collected by filtration and dried to give (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinamide hydrochloride (0.022 g, 0.0419 mmol, 7% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.90 (br s, 1H), 11.35 (br s, 1H), 8.87 (d, 1H), 8.36 (br s, 3H), 8.31 (s, 1H), 8.21-8.11 (m, 3H), 7.74 (t, 1H), 4.04-3.94 (m, 1H), 3.76-3.67 (m, 1H), 3.58-3.48 (m, 1H), 3.43-3.34 (m, 1H), 3.08-3.00 (m, 1H), 2.44-2.37 (m, 1H), 2.27-2.14 (m, 1H), 1.90-1.81 (m, 1H), 1.63-1.51 (m, 1H); LCMS (APCI+) m/z 415.1, 417 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:33])=[C:28]([CH:32]=1)[C:29]([NH2:31])=[O:30]>>[NH2:31][C:29]([C:28]1[CH:32]=[C:24]([NH:23][C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:15][CH:16]=2)=[O:21])[CH:25]=[CH:26][C:27]=1[CH3:33])=[O:30]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: Cc1ccc(N)cc1C(N)=O
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)Nc4ccc(C)c(C(N)=O)c4)cc3)c2)o1

Procedure:
N-(3-Aminocarbonyl-4-methylphenyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 5-amino-2-methylbenzamide using method I. LCMS; retention time 3.00 min, MH+ 427.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:19](CC3C=CC=CC=3)[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH:22]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H][H]>C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[NH:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCCCOc2cc(-c3ccc(OC)c(OC)c3)nn2Cc2ccccc2)cc1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CCNCCCOc2cc(-c3ccc(OC)c(OC)c3)[nH]n2)cc1OC
Yield: 27 %

Procedure:
4.9 g of 3-(3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propyloxy)-2-benzyl-5-(3,4-dimethoxyphenyl)-pyrazole were dissolved in glacial acetic acid, 0.5 g of palladium on charcoal was added, and the reaction mixture was hydrogenated at 80 bar hydrogen pressure and at 80° C. for 24 hours. After removal of the catalyst by filtration, the reaction mixture was concentrated by evaporation and rendered alkaline (pH=10) with sodium hydroxide solution, and the product was extracted with ethyl acetate. The organic phase was separated, concentrated and purified by flash chromatography over silica gel. 1.1 g of 3-{3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propyloxy}-5-(3,4-dimethoxyphenyl)-pyrazole were obtained. The IR spectrum of the base (as film) showed bands at 1511 cm-1, 1465 cm-1, 1262 cm-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[NH:4][C:5](=[O:8])[NH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19]Br.O>C(#N)C>[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][N:4]1[C:3]([O:2][CH3:1])=[N:7][NH:6][C:5]1=[O:8]
Reactant: BrCc1cccc(Br)c1
Reactant: COc1n[nH]c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1n[nH]c(=O)n1Cc1cccc(Br)c1
Reaction time: 6 h
Yield: 29.9 %

Procedure:
To a solution of 2.30 g (20 mmol) of 5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one in 20 ml acetonitrile was added 2.90 g (21 mmol) of potassium carbonate. A solution of 5.00 g (20 mmol) of 3-bromobenzylbromide in 20 ml of dry acetonitrile was added dropwise thereto at 55° C. After the mixture was stirred at the same temperature for additional 6 hours, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the resultant solid residue (5.2 g) was added a mixture of equal amounts of tert-butyl methyl ether and n-hexane and the solid was washed, ice-cooled, collected by filtration and concentrated. Further, to the resultant solid residue was added tert-butyl methyl ether and the solid was washed, cooled, collected by filtration and dried to obtain 1.70 g (5.98 mmol) of 4-(3-bromobenzyl)-5-methoxy-2,4-dihydro-3H-1,2,4-triazol-3-one as white powder.
Reaction SMILES: CO[C:3]([P:5](=[O:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])=[O:4].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15]>O1CCCC1>[NH2:17][C:14](=[N:16][C:3]([P:5](=[O:12])([O:6][CH2:7][CH3:8])[O:9][CH2:10][CH3:11])=[O:4])[CH3:15]
Reactant: CCOP(=O)(OCC)C(=O)OC
Reactant: CC(=N)N
Agent: Cl
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(=O)N=C(C)N

Procedure:
A solution of 98 parts of diethyl methoxycarbonylphosphonate plus 47 parts of acetamidine hydrochloride in 1000 parts of anhydrous tetrahydrofuran can be refluxed for 8 hours and the solvent then removed under reduced pressure to give diethyl 1-amino-1-methylmethyleneaminocarbonylphosphonate. In a similar manner, starting with the appropriate alkoxycarbonylphosphonate and imino compounds, the following compounds can be prepared: