Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH:15]=[CH:16][C:17]3[CH:38]=[CH:37][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:19][CH:18]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].[H][H]>FC(F)(F)C(O)=O.[Pd]>[C:1]([NH:4][C:5]1[N:6]=[C:7]([OH:39])[C:8]2[CH:14]=[C:13]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH:23][C@H:24]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:22])=[CH:37][CH:38]=3)[CH:12]=[N:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C=Cc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(NC(C)=O)nc(O)c3c2)cc1)C(=O)OCC
Yield: 56 %

Procedure:
A solution of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethenyl]benzoyl)-L-glutamate in 30 mL of trifluoroacetic acid was hydrogenated at 55 psi of hydrogen in the presence of 1.0 g of 5% Pd/C at room temperature for 14 hours. The catalyst was removed by filtration, the filtrate evaporated under reduced pressure, and the residual solid partitioned between 100 mL of chloroform and 50 ml of 2N aqueous sodium carbonate. The organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent removed by evaporation to give a gum which was chromatographed on silica gel. Elution with chloroform:methanol (97:3) gave 0.25 g (56%) of diethyl N-(4-[2-(2-acetamido-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate; mp 215°-217° C.; NMR (CDCl3) delta 1.25, 1.35(2t, 6H, J=6 Hz), 2.1-2.5(m, 4H), 2.55(s, 3H), 3.1(s, 4H), 4.15, 4.25(2q, 4H, J=6 Hz), 4.6-4.96(m, 1H), 7.05(s, 1H), 7.25, 7.75(AB q, 4H, J=9 Hz), 8.35(d, 1 H, J=3 Hz), 8.77(d, 1H, J=3 Hz); IR (Nujol) 3200, 3150, 1725, 1675, 1630, 1605 cm-1. Anal.: Calc'd. for C27H31N5O7 : C, 60.32; H, 5.81; N, 13.03. Found: C, 59.98; H, 6.03; N, 12.92).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[C:4]=1[F:25])#[N:2].[CH:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]1[CH3:35])([CH3:28])[CH3:27]>>[F:25][C:4]1[C:5]([CH3:24])=[C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([N:32]4[CH2:33][CH2:34][N:29]([CH:26]([CH3:28])[CH3:27])[C@H:30]([CH3:35])[CH2:31]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)N1CCNC[C@H]1C
Reactant: Cc1c(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccc(C#N)c1F
Product: Cc1c(-c2cnn(-c3ccc(C(=O)N4CCN(C(C)C)[C@H](C)C4)cn3)c2O)ccc(C#N)c1F

Procedure:
The title compound was prepared in a manner similar to Example 303 using 6-(4-(4-cyano-3-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-1-isopropyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18 (d, J=5.81 Hz, 4H) 1.30 (d, J=6.32 Hz, 5H) 2.33 (d, J=2.27 Hz, 3H) 2.85-3.65 (m, 5H) 3.89 (br. s., 2H) 4.20-4.83 (m, 1H) 7.64 (br. s., 1H) 7.70-7.79 (m, 1H) 7.93-8.77 (m, 4H) 9.36-10.10 (m, 1H). ESI-MS m/z [M+H]+ 463.3.
Reaction SMILES: N1CCNCCNCC1.[C:10]1(C)[CH:15]=CC(S(Cl)(=O)=O)=C[CH:11]=1.[C:21]1([CH3:49])[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][N:33]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:41])=[O:40])[CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1.ICCCI.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:11][CH2:10][CH3:15].[C:21]1([CH3:49])[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34][N:33]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=3)(=[O:40])=[O:41])[CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CNCCNCCN1
Agent: Cc1ccc(S(=O)(=O)N2CCNCCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: ICCCI
Solvent: CC#N
Product: CCC

Procedure:
1.1.19 1,3-Bis (1,4,7-triazacyclononane) propane N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.1.20) was prepared by reacting (1.1.3) with two equivalents of p-toluenesulfonyl chloride. Two equivalents of N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane (1.1.20) hydrobromide were reacted with one equivalent of 1,3-diiodopropane in acetonitrile with excess potassium carbonate. 1,3-Bis[N,N′-bis(p-toluenesulfonyl)-1,4,7-triazacyclononane propane (1.1.21) was isolated and purified by chromatography. The p-toluenesulfonyl groups were removed using sulfuric acid and HBr to yield the title compound (1.1.19).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)#[N:11].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1.CO>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]2[CH:16]=[CH:17][C:12]([C:10]#[N:11])=[CH:13][CH:14]=2)=[N:3][CH:4]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COc1ccc(I)nc1
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc(-c2ccc(C#N)cc2)nc1
Yield: 66 %

Procedure:
A mixture of 3.1 g (13.2 mM) of 2-iodo-5-methoxypyridine, 2.9 g (19.8 mM) of 4-cyanophenylboronic acid, 1.7 g (40 mM) of lithium chloride, 0.6 g (0.52 mM) of tetrakis(triphenylphosphine)palladium, 30 ml of methanol and 30 ml of toluene is prepared and 20 ml (40 mM) of 2 M sodium carbonate are added. The reaction mixture is heated at the reflux temperature of the solvent for 72 hours. The phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with N sodium hydroxide solution, with water and with saturated sodium chloride solution and then dried over magnesium sulfate. After evaporation of the solvents, the crude product is purified by chromatography on silica gel using dichloromethane as the eluent to give the expected product in the form of a pale yellow solid with a yield of 66%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OCC)cc1
Yield: 96.2 %

Procedure:
499 mg of 4-ethoxyphenylacetic acid ethyl ester, 480 mg of carbonyldiimidazole, and 0.5 g of 4-methanesulfonyl benzoic acid were dissolved in 10 ml of dimethy formamide, and 119 mg of sodium hydride were slowly added dropwise to the solution and the mixture was reacted at the room temperature for 12 hours. Afterwards, water was added to dilute the resultant, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate to give 0.9 g of the titled compound as a light yellow liquid (yield 92%).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[NH:4][C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:3]=1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Reactant: BrCCOc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1c(-c2cccnc2)n(CCOc2ccccc2)c2ccc(C#N)cc12
Reaction time: 48 h

Procedure:
To a solution of 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6, 47 mg, 0.20 mmol) in THF (5 mL) at room temperature is added KHMDS (0.5 M in toluene, 0.60 mL, 0.30 mmol) followed with (2-bromo-ethoxy)-benzene (90 mg, 0.45 mmol). The mixture is stirred under N2 for 2 days and aqueous ammonium chloride (1 mL) is added to quench the reaction. The volatiles are removed in vacuo and the residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 1:4 to 1:0) to give 3-methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.25 (s, 3H), 4.10 (t, J=5.2 Hz, 2H), 4.46 (t, J=5.3 Hz, 2H), 6.66 (d, J=7.8 Hz, 2H), 6.93 (t, J=7.3 Hz, 1H), 7.17-7.25 (m, 2H), 7.51-7.57 (m, 2H), 7.59-7.65 (m, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.98 (s, 1H), 8.74-8.79 (m, 2H). HRMS (ESI) m/z 354.1618 [(M+H)+ Calcd for C23H20N3O: 354.1606].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[N:4]=1.[S:21](=[O:36])(=[O:35])([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][O:33][CH3:34])[NH2:22].N12CCCN=C1CCCCC2>C(#N)C>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12](=[O:20])[NH:22][S:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][CH2:31][CH2:32][O:33][CH3:34])(=[O:36])=[O:35])[N:6]=1
Reactant: COCCOc1ccccc1OS(N)(=O)=O
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COCCOc1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.4 %

Procedure:
1.74 g (0.0063 mol) of phenyl N-(4,6-dimethoxypyrimidin-2-yl)carbamate are dissolved in 80 ml of acetonitrile, and 1.48 g (0.006 mol) of 2-(2-methoxyethoxy)phenyl sulfamate are added at room temperature. 1.0 g (0.0066 mol) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) are added and the reaction mixture is then stirred at room temperature for 18 hours, concentrated, diluted with H2O and acidified with 2N hydrochloric acid to give a pH of 3-4. After the solids have been filtered off with suction and dried, 2.4 g (93% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-1-[2-(2-methoxyethoxy)phenoxysulfonyl]urea of melting point 106°-108° C. are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl>CC(C)=O>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Fc1ncccc1C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC(C)=O
Product: O=C1CCC(c2cccnc2F)CC1
Temperature: 45 °C

Procedure:
To a solution of 2-fluoro-3-(1,4-dioxaspiro[4.5]decan-8-yl)pyridine (7.88 g, 33.2 mmol) in acetone (350 mL) was added aqueous hydrochloric acid (39.9 mL, 39.9 mmol, 1N). The mixture was heated to 45° C. for 5 h, then cooled to room temperature. Most of the organic solvent was removed in vacuo and ethyl acetate (200 mL) was added. The resulting solution was washed with saturated aqueous sodium bicarbonate (2×), water (1×), saturated aqueous sodium chloride (1×), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give 4-(2-fluoropyridin-3-yl)cyclohexanone. MS (ESI, pos. ion) m/z: 194.1.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(#N)C>[C:6]([O:5][C:3](=[O:4])[CH2:2][NH:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: NCc1ccccc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)CNCc1ccccc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 108 %

Procedure:
40 g (205 mmol, 1 eq.) tert-butyl bromoacetate were dissolved in 200 ml acetonitrile. The solution was cooled to 0-5° C. and 47 g benzylamine (2.14 eq.) in solution in 90 ml acetonitrile were added over 15 min. After 5 min, the reaction mixture was warmed to room temperature and stirred for 3 h (IPC by GC). The resulting suspension was filtered and evaporated to constant weight to give 49 g of a yellow oil. The oil was dissolved in 200 ml heptane and washed 3 times with 50 ml aq. sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate, filtered and evaporated to give 35.8 g of the crude product. Distillation under high vacuum afforded 27.2 g of the titled product (95% pure by GC).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH3:11])(=[O:20])=[O:19]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: Brc1cccc2[nH]ccc12
Product: Cc1ccccc1S(=O)(=O)n1ccc2c(Br)cccc21
Yield: 87 %

Procedure:
The compound was prepared from 4-bromoindole (1.02 g, 5.25 mmol) and o-methylbenzenesulfonyl chloride (a 9:1 mixture of ortho and para methyl isomers) (1.29 g, 6.78 mmol) according to method 4. Purification by column chromatography (SiO2, CH2Cl2:heptane) gave 1.6 g (87%) of the title compound which contains ca 10% of the p-methyl isomer) as a light purple viscous oil: 1HNMR (CD3OD) δ 7.94-6.68 (m, 9H), 2.52 (s, 3H); MS (ESI) 352.3 (M+H)+; Purity (HPLC) >95%.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.O>[NH:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCC1CCNC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
TEA (1.05 mL, 7.5 mmol) was added to a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (1 g, 5 mmol) in DCM (25 mL) at 0° C. Methanesulfonyl chloride (0.43 mL, 5.5 mmol) was then added. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water. The organic phase was separated, dried (MgSO4), filtered and concentrated. The crude material was treated with 1M HCl in MeOH (25 mL) at RT and stirred at RT for 20 h. The volatiles were removed under reduced pressure to afford 0.95 g of 72 as a white solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:29][C:30]#[N:31].CI>O1CCCC1>[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[CH:29]([CH3:1])[C:30]#[N:31]
Reactant: CC(C)NC(C)C
Reactant: N#CCc1cccc(F)c1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 51.5 %

Procedure:
A solution of 1.586 g (16 mmol) diisopropylamine in 25 ml tetrahydrofuran was cooled with sodium chloride/ice to −10° C. A solution of 9 ml (14 mmol) 1.6 M butyl lithium in hexanes was added drop-wise. After stirring for 10 min the resulting LDA solution was cooled to −78° C. and a solution of 2.00 g (13 mmol) 2,3-difluorophenyl-acetonitrile in 5 ml tetrahydrofuran slowly added. The reaction mixture was stirred at −78° C. for 40 min, then 2.22 g (16 mmol) methyl iodide were added and the cooling bath was removed after 5 min. The mixture was stirred for 2.5 h at room temperature, and then aqueous ammonium chloride solution was added. The mixture was extracted twice with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was purified using column chromatography (SiO2, heptanes/ethyl acetate 9:1) to yield 1.12 g of rac-2-(2,3-difluoro-phenyl)-propionitrile as a light yellow liquid; MS (EI): 167.1 (M+.), 152.1 (((M-CH3)+.), 100%).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.C(N(CC)CC)C.[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([OH:31])=O)[C@H:25]([CH2:27][CH3:28])[CH3:26].O.[NH:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:23]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C@H:24]([C:29]([N:40]1[CH2:54][CH2:53][CH2:52][C@@H:41]1[C:42]([O:44][CH2:45][C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:43])=[O:31])[C@H:25]([CH2:27][CH3:28])[CH3:26]
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 72 %

Procedure:
While cooling on ice, DCC (8.3 g, 30 mmol) and triethylamine (3.5 ml, 25 mmol) were added to DMF (200 ml) containing Boc-L-Ile-OH.1/2 H2O (24.0 g, 100 mmol), H-D-Pro-OBzl-HCl (19.3 g, 80 mmol), and HOBt.H2O (15.3 g, 100 mmol). After stirring for 8 hours, DMF was removed by evaporation, the residue was dissolved in ethyl acetate, and then successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. After drying over MgSO4 and concentrating, the resulting oily substance was purified by flash silica gel chromatography (4×30 cm, 1% methanol/chloroform) to obtain the oily title compound (21.5 g, 51 mmol, 72% yield). TLC: Rf=(CHCl3/MeOH=9/1)
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].C(OCC)(=O)C>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][CH2:20][NH:19][C:6]1[C:5]([C:9]([OH:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)=[O:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNc1nc(Cl)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
A solution of 2.21 g (11.45 mmol) of 2,4-dichloro-5-pyrimidinecarboxylic acid prepared in step 2.3 (method B) in 20 mL of anhydrous THF is cooled to 2-5°C. on an ice bath. A solution of 4.79 mL (34.35 mmol) of triethylamine and 2 g (11.48 mmol) of tert-butyl (3-aminopropyl)carbamate in 15 mL of anhydrous THF is then added dropwise. The reaction mixture is stirred at room temperature for 30 minutes. Ethyl acetate is added and the organic phase is washed with aqueous 1N HCl and with water. The organic phases are combined, dried over sodium sulfate, filtered and concentrated under vacuum. 3.35 g of the expected product are obtained in the form of a yellow solid. Yield=88.6%.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4](=[O:16])[O:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][C:8]=1[OH:9].C(O)(=O)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CN(C)C=O>[OH:9][C:8]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:16])[C:3]=1[NH:2][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1c(O)cc(-c2ccccc2)oc1=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1oc(-c2ccccc2)cc(O)c1NCc1ccccc1

Procedure:
The title compound was prepared by method D using 3-amino-4-hydroxy-6-phenyl-2H-pyran-2-one hydrochloride (0.500 g, 2.08 mmol), 1% acetic acid in dimethylformamide (20 mL), benzaldehyde (0.233 mL, 2.29 mmol), sodium cyanoborohydride (0.144 g, 2.29 mmol). m.p. dec. 205° C., 1H NMR (250 MHZ, DMSO-d6) δ 4.37 (s, 2 H), 6.56 (s, 1 H), 7.27 (m, 5 H), 7.45 (m, 3 H), 7.67 (m, 2 H).
Reaction SMILES: C(N(CC)CC)C.C(O)=O.C(OC([CH:17]([C:27](=[O:30])[CH2:28][CH3:29])[C:18]([C:20]1[C:21]([CH3:26])=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19])=O)C=C>C1COCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:26][C:21]1[C:20]([C:18](=[O:19])[CH2:17][C:27](=[O:30])[CH2:28][CH3:29])=[CH:25][N:24]=[CH:23][N:22]=1
Reactant: C=CCOC(=O)C(C(=O)CC)C(=O)c1cncnc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(=O)CC(=O)c1cncnc1C
Yield: 101.7 %

Procedure:
To a suspension of 6.6 mg of palladium diacetate (Pd(OAc)2), triethylamine (226 mg), and formic acid (204 mg) in 2 ml THF was added 410 mg of 2-(allyloxycarbonyl)-1-(4-methylpyrimidin-5-yl)pentan-1,3-dione. The mixture was refluxed for 3.5 hours, cooled and partitioned between ethyl acetate and water. The organic layer was dried with magnesium sulfate, filtered and evaporated to yield 290 mg of 1-(4-methylpyrimidin-5-yl)pentan-1,3-dione as an amber liquid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: NC(=NO)c1ccc(OCCO)cc1
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(OCCO)cc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the general procedure 4 starting from Intermediate 3 and Intermediate 27 affording the product as colorless oil. LC/MS (Method B): 417.3 (M+H)+. HPLC (Method A) Rt 5.43 min (Purity: 96.4%).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[C:13]1([C:19]2[C:23]([CH:24]=O)=[CH:22][NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:24]/[C:23]1[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:20][NH:21][CH:22]=1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1c[nH]nc1-c1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1c[nH]nc1-c1ccccc1
Temperature: 75 °C
Yield: 45.5 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-Phenyl-1H-pyrazole-4-carboxaldehyde (0.18 mmol, 31 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 26 mg of (Z)-5,6-dihydro-5-oxo-4-[(3-phenyl-1H-pyrazol-4-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid. MS(ES): m/e 337 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH3:25])=[O:23])=[N:11][N:12]([CH2:18][C:19](=O)[CH3:20])[C:13]=1[C:14](OC)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10]([C:22]([O:24][CH3:25])=[O:23])=[N:11][N:12]2[CH2:18][CH:19]([CH3:20])[N:27]([CH3:26])[C:14](=[O:15])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nn(CC(C)=O)c(C(=O)OC)c1OCc1ccccc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)C(C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1-(2-oxopropyl)-1H-pyrazole-3,5-dicarboxylate (80 mg, 0.231 mmol) in anhydrous CH2Cl2 were added methylamine (173 μL, 2.0M in THF), sodium triacetoxyborohydride (98 mg, 0.462 mmol), and AcOH (20 μL, 0.346 mmol). The reaction was stirred at room temperature overnight. Toluene was added to replace the evaporated solvent, and the mixture was heated to 110° C. for 3 h. The solvent was removed in vacuo, and purification was achieved by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the title product as a yellow oil. ES MS (M+1)=330.