Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:15][CH2:16][C:17]1[C:18]([F:34])=[C:19]([O:24][C:25]2[CH:26]=[C:27]([CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:28]#[N:29])[C:20]([Br:23])=[CH:21][CH:22]=1.CC(OC([N:42](C(OC(C)(C)C)=O)[C:43]1[NH:44][C:45]([C:49](O)=[O:50])=[C:46]([Cl:48])[N:47]=1)=O)(C)C.[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>CN(C=O)C.ClCCl>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[NH2:42][C:43]1[NH:44][C:45]([C:49]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[C:19]([O:24][C:25]3[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[C:31]([Cl:33])[CH:32]=3)[C:18]=2[F:34])=[O:50])=[C:46]([Cl:48])[N:47]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Cl)c(C(=O)O)[nH]1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CNC(=O)c3[nH]c(N)nc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.2 %

Procedure:
EDC (0.029 g, 0.152 mmol) and HOBT (0.021 g, 0.152 mmol) were added to a solution of 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.049 g, 0.138 mmol) and 2-(bis{[(1,1-dimethylethyl)oxy]carbonyl}amino)-4-chloro-1H-imidazole-5-carboxylic acid (0.050 g, 0.138 mmol) in DMF (2 mL). The mixture was stirred at RT for 1 hr. The reaction mixture was extracted with EtOAc and saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated to an oil. Dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL, 6.49 mmol) were added and the mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0.1% formic acid) to give the title compound (0.0103 g, 18%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (br. s., 1H), 7.75-7.85 (m, 2H), 7.61 (d, 1H), 7.49 (s, 1H), 7.43 (m, 1H), 7.21-7.32 (m, 1H), 5.82 (br. s., 2H), 4.47 (d, 2H). LCMS: m/z 499 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:27])[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])[N:13]=1)[CH2:2][CH2:3][CH3:4]>CO.[Pd]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N:18]([CH3:27])[C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:20])[N:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCCCC)n1
Agent: [Pd]
Solvent: CO
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)n1
Yield: 86 %

Procedure:
A solution of 430 mg of methyl(E)-3-{3-butoxy-4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate in 5 mL of methanol is stirred for 3 hours at room temperature in the presence of 100 mg of palladium-on-charcoal, under a hydrogen atmosphere. After filtering off the palladium and evaporating off the solvents, 370 mg of methyl 3-{3-butoxy-4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}propionate are obtained. Yield=86%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8](Cl)[C:7]=1[N+:14]([O-:16])=[O:15])[CH3:2].[NH3:25]>C1COCC1>[CH2:1]([O:3][C:4](=[O:24])[N:5]([C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([NH2:25])[C:7]=1[N+:14]([O-:16])=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:2]
Reactant: N
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Solvent: C1CCOC1
Product: CCOC(=O)N(Cc1ccccc1)c1cc(Cl)nc(N)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Benzyl-(2,6-dichloro-3-nitro-pyridin-4-yl)-carbamic acid ethyl ester (500 mg) was dissolved in THF (3 ml) in a ReactiVial. Ammonia (7M in MeOH, 1 ml) was added, the vial was sealed, and the reaction left to stir at RT for 48 h. The reaction mixture was then pre-absorbed directly onto silica and columned on Isco Companion on a silica column (40 g, Redisep), eluting with EtOAc:heptane, increasing the gradient linearly from 10:90 to 40:60 over 10 column volumes. The desired fractions were combined and evaporated to provide the title compound as a yellow gum which solidified on scratching (305 mg)
Reaction SMILES: [C@]12(C)C(C)(C)C(CC1)CC2C([O:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25])[C:14]([CH3:17])([CH3:16])[CH3:15])=O.C([O-])([O-])=O.[K+].[K+].O.Cl>CO>[N+:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:13]([OH:12])[C:14]([CH3:16])([CH3:15])[CH3:17])([O-:26])=[O:25]
Reactant: CC(C)(C)C(OC(=O)C1CC2CC[C@]1(C)C2(C)C)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)C(O)c1ccccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
A mixture of single diastereomer (R or S)-1-(2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (658 mg, 1.68 mmol) and K2CO3 (241 mg, 1.74 mmol) in methanol (23 mL) was heated to reflux for 30 minutes. Water (5 mL) was added and the solution was neutralized to pH 7 with 1M HCl. Solvent was removed in vacuo and the residue was taken into a mixture of ethyl acetate (20 mL) and water (10 mL). The organic phase was separated, dried over anhydrous Na2SO4, concentrated in vacuo and purified by silica gel column chromatography to yield single enantiomer (R or S)-1-(2-nitrophenyl)-2,2-dimethyl-1-propanol (325 mg, 92%) as a light yellow oil. 1H NMR was identical to that of the racemic alcohol. The absolute configuration of the single enantiomer alcohol is not determined.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([NH2:9])=[O:8])[CH3:2].Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:9]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOc1ccc(C(N)=O)cc1OCC
Product: CCOC(=O)c1coc(-c2ccc(OCC)c(OCC)c2)n1
Yield: 85 %

Procedure:
Using 10.4 g of 3,4-diethoxybenzamide and 19.5 g of ethyl 3-bromo-2-oxopropionate and following the procedure of Reference Example 5, 12.9 g of white powdery ethyl 2-(3,4-diethoxyphenyl)oxazole-4-carboxylate was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([O:22]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:3]1.[NH3:34]>C1COCC1>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[C:4]([C:20]([NH2:34])=[O:22])=[CH:3]1
Reactant: Cn1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(Nc2ccc3ccccc3c2)cc1=O
Reactant: N
Solvent: C1CCOC1
Product: Cn1cc(C(N)=O)c(Nc2ccc3ccccc3c2)cc1=O
Yield: 87 %

Procedure:
2,3,4,5,6-Pentafluorophenyl 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxylate in THF was reacted with conc. NH3 solution as for example 37, step B. The crude product was recrystallised (MeOH/EtOAc) to give 1-methyl-4-(2-naphthylamino)-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a white solid (87%); m.p. (MeOH/EtOAc) 254-257° C. 1H NMR [400 MHz, (CD3)2SO] δ 10.56 (s, 1H), 8.35 (s, 1H), 7.95-7.86 (m, 4H), 7.74 (d, J=1.9 Hz, 1H), 7.53-7.42 (m, 3H), 7.39 (dd, J=8.7, 2.1 Hz, 1H), 5.86 (s, 1H), 3.37 (s, 3H). LCMS (ACPI−) 292 (100%). Anal. Calcd for C17H15N3O2: C, 69.6; H, 5.2; N, 14.3. Found C, 69.4; H, 5.2; N, 14.5.
Reaction SMILES: [CH3:1][C:2]1[O:11][C:10](=[O:12])[C:9]2[C:8](=[O:13])[CH2:7][CH:6]([CH:14]([CH3:16])[CH3:15])[O:5][C:4]=2[CH:3]=1.O.[OH-].[Na+].Cl>C(OC)(C)(C)C>[OH:5][C:4]1[CH:3]=[C:2]([CH3:1])[O:11][C:10](=[O:12])[C:9]=1[C:8](=[O:13])[CH:7]=[CH:6][CH:14]([CH3:15])[CH3:16]
Reactant: Cc1cc2c(c(=O)o1)C(=O)CC(C(C)C)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: O
Product: Cc1cc(O)c(C(=O)C=CC(C)C)c(=O)o1
Reaction time: 4 h
Yield: 43.4 %

Procedure:
To a mixture of 189 mg of 2,3-dihydro-7-methyl-2-(1-methylethyl)- 4H, 5H-pyrano[4,3-b]pyran-4,5-dione, 4mloftoluene and 4 ml of water, 0.20 g of sodium hydroxide was added and stirred. After 4 hours, methyl t-butyl ether and 3% hydrochloric acid were added to the reaction mixture. The separated organic layer was washed with saturated brine once, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 82 mg of 4-hydroxy-6-methyl-3-(4-methyl-2-pentenoyl)-2-pyrone.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1Cl)[C:7]#[N:8])([O-:3])=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:7]([C:6]1[CH:9]=[CH:10][C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)#[N:8]
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccc(NCCCCO)c([N+](=O)[O-])c1
Temperature: 23 °C
Reaction time: 12 h
Yield: 98.7 %

Procedure:
A mixture of 3-nitro-4-chloro-benzonitrile (20.4 g, 112.2 mmol), and 4-aminobutanol (10 g, 112 mmol) and K2CO3 (30.9 g, 224 mmol) in CH3CN (100 ml) was stirred at 23° C. for 12 h. Starting material remains by TLC analysis. Additional 4-aminobutanol (2 g, 22 mmol) was added and stirring continued for 24 h. The mixture is filtered and concentrated. The residue is dissolved in EtOAc and washed with water. The extracts are dried over MgSO4 and concentrated to give 26 g (99%) of 4-(4-cyano-2-nitro-phenylamino)-butan-1-ol as an orange solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1>N1C=CC=CC=1.[Cu]=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:14][C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: Brc1ccccn1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: COC(=O)Cc1cccc(Oc2ccccn2)c1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
2-Bromopyridine (1.1 ml, 11.5 mmol) and potassium carbonate (2.76 g, 20.0retool) were added to a solution of methyl 3-hydroxyphenylacetate (1.66 g, 9.99 mmol) in anhydrous pyridine (12 ml). The vigorously stirred reaction mixture was heated to 90° C. under a nitrogen atmosphere and then copper (II) oxide (1.99 g, 25.0 mmol) was added under a positive nitrogen flush. The reaction mixture was heated under reflux for 16 hours, allowed to cool and diluted with dichloromethane. The mixture was filtered through hyflo and concentrated in vacuo. The residue was purified by flash chromatography on silica eluting with 1:3 ethyl acetate/petrol (60°-80°) then 1:2 ethyl acetate/petrol (60°-80°) to give methyl [3-(2-pyridyloxy)phenyl]acetate as a pale straw-coloured oil (1.85 g, 78%); δH (360MHz, CDCl3) 3.63 (2H, s, CH2), 3.69 (3H, s, COOCH3), 6.90 (1H, d, J 8 Hz, ArH), 6.99 (1H, m, ArH), 7.06 (2H, m, ArH), 7.11 (1H, d, J 8 Hz, ArH), 7.34 (1H, t, J 8 Hz, 5'-H), 7.67 (1H, m, ArH), 8.19 (1H, m, 6"-H), m/z 243 (M+).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[NH:15][N:16]=[C:17]([CH3:19])[N:18]=1)[N:7]=3.O1CCCCC1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1>>[CH3:19][C:17]1[N:18]=[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:20]=[CH:21][C:2]([C:34]5[CH:33]=[N:32][N:31]([CH2:30][CH2:29][OH:28])[CH:35]=5)=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)[NH:15][N:16]=1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Reactant: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n1
Product: Cc1n[nH]c(-c2cn3c(n2)-c2ccc(-c4cnn(CCO)c4)cc2OCC3)n1

Procedure:
8-Bromo-2-(5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene was reacted with 1-[2-(Tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole under microwave conditions to give 254. MS(ESI+) 378.2
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][CH3:33])[CH2:46][CH2:45]1)=[O:20]
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Reactant: COc1ccccc1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(OC(F)(F)F)c3)noc2N)CC1
Yield: 73.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (622 mg, 1.35 mmol, 73%) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][OH:32])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10].[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:33])([CH2:31][O:32][S:35]([CH3:34])(=[O:37])=[O:36])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:29])([F:28])[CH:25]([F:26])[F:27])=[CH:18][CH:17]=2)[C:12]1=[O:30])[CH3:10]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.90 g) was dissolved in 30 ml of ethyl acetate, to which 0.69 g of methanesulfonyl chloride and 0.61 g of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (20 ml×2) and 10 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 2.2 g of 1-[(1R,2S)-2-(2-fluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]3[N:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:24])[C:18]4=[C:17]([OH:28])[C:16](=[O:29])[N:15]=3)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Pd]>[OH:28][C:17]1[C:16](=[O:29])[N:15]=[C:14]([CH2:13][C:8]2([C:5]3[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=3)[CH2:9][CH2:10][CH2:11][CH2:12]2)[N:19]2[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[C:23](=[O:24])[C:18]=12
Reactant: CC(C)N1CCn2c(CC3(c4ccc(Cl)cc4)CCCC3)nc(=O)c(O)c2C1=O
Agent: [Pd]
Product: CC(C)N1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(O)c2C1=O
Reaction time: 9 h
Yield: 54.5 %

Procedure:
To a stirred solution of 6-[1-(4-chlorophenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (32-03) (350 mg, 0.842 mmol) was added 35 mg 10% Pd—C. Hydrogenation was conducted by balloon pressure at room temperature for 9 h. After completion of the reaction, the mixture was filtered over a celite bed, which was washed with methanol, followed by 10% methanol in dichloromethane. The filtrate was concentrated to a pasty mass, which was washed with ether, followed by pentane to get 9-hydroxy-2-isopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (32-04) (175 mg, 54.5%) as a yellow solid.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]([N:19]([CH:21]([CH3:23])[CH3:22])[CH3:20])[C:16]([OH:18])=O)=[CH:11][CH:10]=1)=O)(C)(C)C.ON1[C:29]2[N:30]=[CH:31]C=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CNC.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C@H:15]([N:19]([CH:21]([CH3:22])[CH3:23])[CH3:20])[C:16]([N:30]([CH3:31])[CH3:29])=[O:18])=[CH:13][CH:14]=1
Reactant: CC(C)N(C)[C@H](C(=O)O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N(C)[C@H](C(=O)N(C)C)c1ccc(N)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 22 (116 mg, 0.36 mmol), 1-hydroxy-7-azabenzotriazole (50 mg, 0.37 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (208 mg, 1.08 mmol) and DMF (2 mL), and the mixture was cooled to 0° C. A 2M solution of dimethylamine in THF (0.3 mL, 0.6 mmol) was added, and the reaction was allowed to warm slowly to room temperature overnight. A solution of potassium carbonate (2.00 g) in water (10 mL) was added, and the mixture was extracted with hexanes (3×30 mL). The hexanes extracts were combined, dried over sodium sulfate, filtered, and evaporated to dryness. The resulting crude product was mixed with methylene chloride (1 mL) and 4M solution of hydrogen chloride in dioxane (10 mL). The resulting emulsion was vigorously stirred for 1 h at room temperature. After this time, the solvents were evaporated under reduced pressure, and the resulting residue was treated with water (2 mL) followed by potassium carbonate (1.0 g), and then extracted with MtBE (10 mL). The extract was evaporated and the residue was purified by flash chromatography on silica gel to afford a 58% yield (53 mg) of 23 as a light yellow oil: 1H NMR (300 MHz, CDCl3/CD3OD) δ 7.20 (d, 2H, J=8.5 Hz), 6.69 (d, 2H, J=8.5 Hz), 4.56 (s, 1H), 3.02 (s, 3H), 2.97 (m, 1H), 2.91 (s, 3H), 2.11 (s, 3H), 1.03 (d, 3H, J=6.7 Hz), 1.00 (d, 3H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=O)[CH3:12])[S:5][C:6]=1[CH3:7].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:7][C:6]1[S:5][C:4]2[CH2:8][CH2:9][N:10]=[C:11]([CH3:12])[C:3]=2[C:2]=1[CH3:1]
Reactant: CC(=O)NCCc1cc(C)c(C)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1=NCCc2sc(C)c(C)c21

Procedure:
In close analogy to the procedure described above, N-[2-(4,5-Dimethyl-thiophen-2-yl)-ethyl]-acetamide is reacted with phosphorus pentoxide to provide the title compound.
Reaction SMILES: C([O:8][NH:9][C:10](=[O:26])[C:11]([NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])([CH3:13])[CH3:12])C1C=CC=CC=1>CO.[Pd]>[OH:8][NH:9][C:10](=[O:26])[C:11]([NH:14][S:15]([C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)(=[O:17])=[O:16])([CH3:13])[CH3:12]
Reactant: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)NOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)NC(C)(C)C(=O)NO)cc1
Reaction time: 1.5 h

Procedure:
A solution of N-benzyloxy-2-(4-methoxybenzenesulfonylamino)-2-methyl-propionamide (1.40 grams, 3.70 mmole) in methanol (80 mL) was treated with 5% palladium on barium sulfate (0.75 grams) and hydrogenated at 3 atmospheres pressure for 1.5 hours in a Parr shaker. The catalyst was removed by passage through a 0.45 μm nylon filter and the filtrate was concentrated to afford N-hydroxy-2-(4-methoxy-benzenesulfonylamino)-2-methylpropionamide as a white solid, 1.06 grams (100%). MP: 122-125° C. MS: 289 (M+1): Analysis calculated for C11H16N2O5S: C, 45.82; H, 5.59; N, 9.72; Found: C, 45.88; H, 5.60; N, 9.69.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]2\[C:18](=[O:27])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[NH:12][C:11]=1[CH3:28])=[O:9].CCN(C(C)C)C(C)C.[CH3:38][C:39](Cl)=[O:40]>>[C:39]([N:5]1[CH2:6][CH:2]([OH:1])[CH:3]([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]3\[C:18](=[O:27])[NH:19][C:20]4[C:25]\3=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[NH:12][C:11]=2[CH3:28])=[O:9])[CH2:4]1)(=[O:40])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CNCC1O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(O)C(NC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To the solution of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-pyrrolidin-3-yl)-amide (150 mg, 0.39 mmol) and DIEA (89 mg, 0.69 mmol) was added CH3COCl (33.7 mg, 0.43 mmol) on an ice bath. The mixture was stirred at r.t. for 3 hrs. After the reaction was complete, DMF was evaporated under reduced pressure and the residue was triturated with methanol and the solid was collected by filtration, washed with ethanol and dried in vacuum to give title compound (82 mg, 57% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.67 (s, 1H), 10.87 (s, 1H), 8.07-8.10 (d, 1H), 7.71-7.85 (m, 3H), 6.82-6.92 (m, 2H), 5.34-5.44 (dd, 1H), 4.13-4.18 (d, 2H), 3.67-3.81 (m, 4H), 2.38-2.40 (ds, 6H), 1.92-1.93 (d, 3H). LC/MS: 427.0 [M+H]+.
Reaction SMILES: O1CCCCC1[N:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1>Cl>[NH:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1
Reactant: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Agent: Cl
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4nc[nH]n4)nc3)cnc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34 %

Procedure:
A mixture of 6-(6-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one in methanolic hydrochloride solution was stirred at room temperature for 0.5 h. The solvent was evaporated under reduced pressure to give the crude product, which was washed with N,N-dimethylformamide to afford the title compound as a hydrochloride salt in 34% yield. 1H NMR (DMSO-d6, 400 MHz) δ (ppm) 11.44 (s, 1H), 9.30 (s, 1H), 8.59 (d, J=8.4 Hz, 1H), 8.46 (s, 1H), 8.22 (m, 2H), 4.70 (t, J=10 Hz, 1H), 4.16 (s, 1H), 3.99 (m, 4H), 3.51 (t, J=11.2 Hz, 2H), 1.86 (m, 2H), 1.69 (d, J=12.8 Hz, 2H); MS (ESI) m/z 379.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]([CH3:11])[CH3:10].Cl.[N:22]([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([C:12]([C:4]2[CH:5]=[CH:6][C:7]3[N:8]([CH:9]([CH3:10])[CH3:11])[N:22]=[N:1][C:2]=3[CH:3]=2)=[O:13])=[CH:19][CH:18]=1
Reactant: CC(C)Nc1ccc(C(=O)c2ccc(F)cc2)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)n1nnc2cc(C(=O)c3ccc(F)cc3)ccc21
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred and cooled (5° C.) solution of 12.3 parts of [3-amino-4-[(1-methylethyl)amino]phenyl](4-fluorophenyl)methanone in 150 parts of a hydrochloric acid solution 6N were added 4.7 parts of sodium nitrite. Upon complete addition, stirring was continued for 1 hour at room temperature. The mixture was treated with a potassium carbonate solution to pH 9 and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 17 parts (100%) of (4-fluorophenyl) [1-(1-methylethyl)-1H-benzotriazol-5-yl]methanone as a residue (int. 3).